Biomimetically Designed Modular Microfluidic-Based Capillaries &amp; Lymphatic Units for Kidney &amp; Liver Dialysis Systems, Organ Bio-Reactors and Bio-Artificial Organ Support Systems

ABSTRACT

A technology that provides various modular biomimetic microfluidic modules emulating varieties of microvasculature in body. These microfluidic-base capillaries and lymphatic Technology modules are constructed as multilayered-microfluidic microchannels of various shapes, and aspect ratios using diverse biocompatible microfluidic polymers. Then, various semipermeable membranes are sandwiched in between these multilayered microfluidic microchannels. These membranes have different chemical, physical characteristics and MWCO values. Consequently, this design will produce much smaller dimension channels similar to human vasculature to achieve biomimetic properties like of human organs and tissues. By interchanging microfluidic-layers or the membranes various diverse modules are designed that act as building blocks for constructing various medical devices, various forms of dialysis devices including albumin and lipid dialysis, water purification, bioreactors bio-artificial organ support systems. Connecting various modules in diverse combinations, permutations, in parallel ad/or in series to ultimately design many unrelated medical devices such as dialysis, bioreactors and organ support devices.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional patent application of U.S. applicationSer. No. 15/060,251 filed on Mar. 3, 2016, the entire contents of whichare hereby incorporated by reference.

FIELD OF THE INVENTION

The landmark HEMO study suggests that the current “urea-centric”approach to renal replacement therapy, delivered in the form of thriceweekly HD, does not reduce morbidity and mortality when clearance ofurea and small molecular uremic toxins is increased beyond existingclinical guidelines, and the maximum survival benefit using thismodality may have already been achieved. Dialysis adequacy shouldideally be broadened to incorporate clearance of middle molecular weighturemic toxins along with small solutes, extracellular fluid volume andblood pressure control, electrolyte and acid base control, correction ofanemia, and optimization of nutritional status and quality of life.Studies that have explored increased frequency, increased length, andinfluence of location (home vs. in-center dialysis), have largelyfocused on existing HD and PD modalities

Since current dialysis modalities which are used to treat ESRD patientshave such disappointing outcomes, there is an urgent need to improve thecurrent dialysis technologies to achieve better QOL and outcomes forthese patients. In addition, the hollow Fiber Technology that iscurrently in use in all forms of dialysis replacement is highlyinefficient and needs to be replaced

In the past decade, the quality of dialysis water has been improved withthe advances in water preparation, and also with advances in monitoringand disinfection methods As a result, high standards are now readilyachievable in clinical practice. Dialysate water can be contaminated bydangerous chemical and microbiological factors, all of which aretheoretically hazardous to patients on any form of renal replacementtherapies. The chlorine compounds are used to suppress bacterial growthin the water supply and then are removed when the water is treated andprepared for hemodialysis/renal replacement therapies. In standard andconventional dialysate preparation, it is almost impossible tocompletely prevent bacterial proliferation in the treated water andultimately from the final dialysate fluid. Hence, conventional dialysatecontains some low level of contamination such as microbiological andfragments of endotoxins meets the required quality standards, it usuallycontains some low level of microbiological contamination, includingbacterial fragments, fragments of endotoxin andpeptidoglycans-collectively referred to as “cytokine-inducingsubstances”. This is due to the fact that the cytokine inducingsubstances cross both low-flux and high-flux hemodialysis membranes andstimulate cytokine production by inflammatory cells.

As a result, advances in dialysis membrane technology have refocusedattention on water quality and its potential role in thebio-incompatibility of hemodialysis circuits and adverse patientoutcomes. The role of ultrapure dialysate is increasingly beingadvocated, given its proposed clinical benefits and relative ease ofproduction as a result of the widespread use of reverse osmosis andultrafiltration. The use of dialysate of much higher microbiologicalpurity improved this state of inflammation. General markers ofinflammation such as serum C-reactive protein (CRP), ferritin, orfibrinogen are commonly used, but the oxidative stress referred toexcessive production of reactive oxygen species (ROS) and inadequateantioxidant protection, is more sensitive, specific, and precocious ofinflammation state. This condition leads to structural and/or functionaldeterioration in cell components including DNA, proteins, carbohydrates,and lipids. The presence of ROS can cause damage in many molecules, suchas lipids, leading to the production of malondialdehyde (MDA), anindicator of lipid peroxidation. In chronic renal failure (CRF) patientsunder hemodialysis (HD) treatment, the formation of ROS is amplified,therefore beyond uremic toxins.

Anytime that a consumable article/element can be manufactured on demandand at a specific location such as in far forward locations; it willlessen the burden on military or the entity for the supply chain. It isevident that items like i.v. fluids are perfect requirements thattechnological solutions can fulfill. In addition other issues such asremoval from the shipping container, or long term storage, could putsome stress on the availability of the i.v. fluids where and when it isneeded. It is preferable that the system should be operational within 45minutes with a preferred goal of less than 20 minutes.

Hence, on demand intravenous (i.v.) fluid resuscitation is not onlycritical but also a vital therapeutic treatment capability that anymedical personnel must have in order to perform the life-savingprocedures. The requirement for easy as well as expedited access todifferent types of i.v. fluid solutions as well as capability toadminister these i.v. fluid solutions to the patients is of paramountimportance and throughout military battle operations.

Currently, the military services meet this requirement by transportingprepackaged i.v. solutions to forward-deployed medical elements andlocations, using valuable airlift capacity to haul what are largelywater. The climactic conditions in forward-deployed locations oftenexpose i.v. fluids to temperatures outside recommended limits forextended periods of time. Extreme weather conditions combined withlimited environmentally controlled storage increases shelf-life andtransport risks, frequently resulting in i.v. fluid disposal andlogistical re-supply operations.

Those skilled in the art will recognize that Hollow Fiber Membranes weredeveloped in the 1960's. They are constructed of a microporous structurehaving a dense selective layer on the outside surface. Many fibers mustbe packed into bundles and potted into tubes to form a membrane module.Modules with a surface area of even a few square feet may require manymiles of fibers. Because a module must contain no defective or brokenfibers, production requires strict quality control. Hollow fibermembranes can withstand very high pressures from the outside, but arelimited on pressure exerted from the inside of the fiber, thereforebackwash rates are limited to around twice the normal permeate rate. Thefeed fluid is applied on the outside of the fibers and the permeate Ifiltrate is removed down the fiber. Hollow Fiber membranes are alsoapplied in clean water applications and are used in membrane bioreactor(MBR), but are limited to lower concentrations of solids than othermembrane types.

This invention is based on a core technology that provides modular,adjustable and scalable microfluidic chipsets units/modules/modules(these terms are used interchangeably throughout the document) that makenumerous basic units that emulate different varieties of capillaries andlymphatic in human body. This biomimetically designed, modular andscalable microfluidic-based capillaries and lymphatic Technology (MCALTechnology) is constructed by manufacturing microfluidic-based multitudeof micro-channels of various shapes (straight, parallel, crisscross,fractal, loop, and branched), forms and configuration with variousaspect ratios using diverse types of inert and biocompatiblemicrofluidic polymer substrates used to manufacture microfluidicsystems. Then using diverse types of semipermeable membranes which havedifferent chemical and physical characteristics and molecular weight cutoff values to construct two or more layer constructs in which varioussemipermeable membranes are sandwiched in between a couple or multiplelayers of these microfluidic layers containing varieties ofmicro-channels with different aspect ratios and configurations. As aresult this design and construct, the core technology will producesmaller dimension channels that can approach human capillaries andlymphatic to achieve biomimetic properties. By changing the microfluidiclayers and/or the semipermeable membranes this core technology willprovide an array of different types of microfluidic-based chipsetunits/modules/modules which are the basic building blocks forconstructing different medical devices with much higher efficiency suchas many different forms of dialysis, water purification, bioreactors,bio-artificial organ support systems Since each basic unit/module/moduleis emulating different types of capillaries or lymphatic, the finalconstruct of the desired medical device would be biomimetic. Thisinvention is called Microfluidic-Based Capillaries and LymphaticTechnology (MCAL Technology) which will allow design and development ofvarious biomimetic devices and ultimately replace the 50 year-oldinefficient hollow fiber technology currently in use.

Furthermore, these basic units/modules/modules can be used in modularand adjustable fashion and hence it is scalable and can be adjusted tomany different and wide-ranging body sizes, various organ supportrequirements and great deal of related and unrelated medical conditionsand illnesses. These basic modules can be connected in parallel and/orin series to design different types of simple and complex medicaldevices with totally different functions. For example, usingMicrofluidic-Based Capillaries and Lymphatic Technology (MCALTechnology) and its various microfluidic-chipset basicunits/modules/modules in different combinations and permutations severalcomplex medical devices and support systems have been designed which areas follow:

#1. Combined microfluidic-based kidney and Liver dialysis device forMulti-organ Dysfunction Syndrome (MODS) and/or Sepsis#2. Mobile, modular and scalable microfluidic-based kidney or liverdialysis systems#3. Microfluidic-based Organ Bio-Reactors for various organ/tissuesupport systems#4. Bio-Artificial organ support systems (combinations of #3 with either#1 or #2)#5. Microfluidic based on demand Intravenous Fluid and dialysateGenerator: For generating ultrapure water from tap water for intravenoususe or dialysate use . . . This will allow to generate different typesof i.v. fluids for medical use.

More so, the modular microfluidic basic building block units will beused to construct several different types of highly efficient dialysissystems which can range from portable to small footprint, wearable,adjustable and lightweight hemodialysis device with capability of liverdialysis and kidney dialysis. This devices utilize a plurality ofmicrofluidic units arranged in modular configuration for efficientdialysis of blood or plasma and for dialysate generation or regenerationof spent dialysate; whereby the microfluidic units comprise a bloodmicrofluidic chip and a dialysate microfluidic chip having integratedmicro-pumps for continuous pumping of blood and dialysate, micro-valvesfor determining flow direction of the blood and dialysate, and aplurality of micro-channels that emulate the natural microvasculature ofthe body for optimal flow of blood and dialysate; whereby the bloodmicrofluidic chip and the dialysate microfluidic chip are separated by asemipermeable membrane; whereby a microfluidic dialysis regeneratingunit independently regenerates spent dialysate for use by themicrofluidic units (Optional).

Furthermore, the present invention relates generally to usingcombinations and permutations of biomimetically designedmicrofluidic-based MCAL Technology chipset units to design artificialkidney and/or liver dialysis devices, bio-artificial kidney and/or liverdialysis devices, and on demand i.v. fluids and dialysate generationdevices. The present invention relates generally to utilizing variouscombinations and permutations of these biomimetically designedmicrofluidic-based MCAL Technology chipset units to design andmanufacture a.) a modular microfluidic systems that are designed to docombined kidney and/or liver dialysis system b) microfluidic Bioreactorfor organ support systems, and c) combination of a.& b for constructingvarious Bio-Artificial Dialysis/organ support systems and d) on demandmicrofluidic i.v. fluid and dialysate generation systems.

The micro-channels designed in the various chipset units (also calledmodules or modules) that are designed and manufactured based on the MCALTechnology. The biomimetically designed microfluidic-based capillariesand lymphatics chipset units/modules of the MCAL Technology) areconfigured to emulate the capillaries and/or lymphatics, which are thesmallest and most fragile of the body's blood vessels. Those skilled inthe art will recognize that the capillaries are responsible for what isknown as microcirculation, meaning that they create a circulatorynetwork within the organs of the body. The role of the capillary is toconnect the arterioles and the venules. Arterioles are small bloodvessels that branch out from arteries, while the venules branch out fromveins. Arteries are the vessels that carry clean, nutrient- andoxygen-rich blood from the heart to the remainder of the body. Veinscarry the blood back to the heart once the nutrients have been absorbedby the various cells and tissues of the body. Each individual capillarydoes not work alone, as these vessels form a network in order to carryout their role in the circulatory system.

BACKGROUND OF THE INVENTION

Capillaries are the smallest and most fragile of the body's bloodvessels ranging from normally round 3-4 μm, but some capillaries can be30-40 μmin diameter. They are responsible for what is known asmicrocirculation-they create a circulatory network within the organs ofthe body. Each individual capillary does not work alone, as thesevessels form a network in order to carry out their role in thecirculatory system. They allow the exchange of nutrients and wastesbetween the blood and the tissue cells, together with the interstitialfluid. This exchange occurs by passive diffusion and by pinocytosiswhich means ‘cell drinking’. Pinocytosis is used for proteins, and somelipids. There are three different types found in the human body: 1)continuous, 2) fenestrated, and 3) sinusoidal. The differences in thevarious types are due to their location in the body as well as theirparticular function.

I. Continuous

The endothelial cells provide an uninterrupted lining, and they onlyallow smaller molecules, such as water and ions to pass through theirintercellular clefts.

II. Fenestrated

Fenestrated capillaries allow extensive molecular exchange with theblood such as the small intestine, endocrine glands and the kidney. The‘fenestrations’ are pores that will allow larger molecules though. Thesetypes of blood vessels are primarily located in the endocrine glands,intestines, pancreas, and glomeruli of kidney.

III. Sinusoidal

Sinusoidal capillaries are special types of open-pore capillary havelarger pores (30-40 μmin diameter) in the endothelium. These types ofblood vessels allow red and white blood cells (7.5 μm-25 μm diameter)and various serum proteins to pass aided by a discontinuous basallamina.

Lymphatics:

Similarly, the lymphatic system is a network of tissues and organs thathelp rid the body of toxins, waste and other unwanted materials. Theprimary function of the lymphatic system is to transport lymph, a fluidcontaining infection-fighting white blood cells, throughout the body.Overall, the lymphatic system is part of the circulatory systemcomprising a network of lymphatic vessels that carry a clear fluidcalled lymph directionally towards the heart Lymphatic vessels, locatedthroughout the body, are larger than capillaries.

Biomimetic:

Biomimetic is the study of the structure and function of biologicalsystems as models for the design and engineering of materials andmachines. Designs formulated using biologically inspired principles willbe used to design and develop a biomimetic tissues (i.e. capillaries,lymphatics), and ultimately human organ structures such as (nephron,glomeruli, alveolus) to simulate the biological functions such asfiltering and detoxifying clearing of toxins from blood usingnon-biological or biological (bioengineered) devices.

Recent technological advances have brought a greater understanding offundamental properties and processes and it has become possible toattempt to'mimic'or synthesize what nature does naturally. This field,now known as biomimetics, covers many new and emerging topics and offerssignificant potential in the further development of MEMS, microfluidicdevices, and lab-on-a-chip systems. Biomimetic designs can encompasssurface treatments that mimic physiological processes or use biologicalprinciples to enhance performance through geometric optimization.

One example that could play a significant role in improved flow controlthrough microfluidic devices is mimicking the structure of vasculartrees and lymphatics. Biological systems of blood vessels are usuallyarranged in hierarchical structures and a distinctive feature of thisarrangement is their multi-stage division or bifurcation. At eachgeneration, the characteristic dimension of the vascular modules willgenerally become smaller, both in length and diameter Similarconfigurations occur in a microfluidic manifold 156 with the inletchannel 158 branching into smaller channels 160 as illustratedschematically in FIG. 8B. It should be noted that this is just oneconfiguration, and these branching can take different forms, topologiesand various configurations such as crisscrossing, fractal, curvilinearetc. In addition, the inlet and outlet will have several designincluding a ledged design to control the distribution hydraulicresistance to be three orders of magnitude lower than the forward flowresistance in the permeation region This means that there will be almostno non-uniformity in the pressure laterally across the permeationregion.

Generally, microfluidics is the science of designing, manufacturing, andformulating devices and processes that deal with volumes of fluid on theorder of microliters or nanoliters. The microfluidic devices often havedimensions ranging from millimeters down to micrometers. Microfluidicsystems have diverse and widespread potential applications. Someexamples of systems and processes that might employ this technologyinclude inkjet printers, blood-cell-separation equipment, biochemicalassays, chemical synthesis, genetic analysis, drug screening,

and mechanical micro-milling. In many instances, the medical industryhas shown keen interest in microfluidics technology.

It is known that microfluidics technology is especially useful for heatand mass transfer applications. For the dialysis of blood, orhemodialysis, the purification of blood external to the body, is aprocess used to treat renal failure. The chemical composition of bloodmust be controlled to perform its essential functions of bringingnutrients and oxygen to the cells of the body, and carrying wastematerials away from those cells. Dialysis replaces some of the kidney'simportant functions. However, currently there is no efficient liverdialysis available for clinical use toe able to replace many of theimportant functions of the liver. Generally, dialysis works on theprinciples of the diffusion and convection of solutes andultrafiltration of fluid across a semi-permeable membrane.

Generally, blood contains particles of many different sizes and types,including cells, proteins, dissolved ions, and organic waste products.Some of these particles, including proteins such as hemoglobin andalbumin, are essential for the body to function properly. Often indialysis, blood flows by one side of a semi-permeable membrane, and adialysate, or special dialysis fluid, flows by the opposite side.Smaller solutes and fluid pass through the membrane, but the membraneblocks the passage of larger substances, such as red blood cells, largeproteins This replicates the filtering process that takes place in thekidneys, when the blood enters the kidneys and the larger substances areseparated from the smaller ones in the glomerulus.

Schematic diagram of a bifurcating vascular network is illustrated inFIG. 4A.

Those skilled in the art will recognize that branching structures foundin mammalian circulatory and respiratory systems, minimizes the amountof biological work required to operate and maintain the system. Arelationship between the diameter of the parent branching vessel and theoptimum diameters of the daughter vessels was first derived by Murrayusing the principle of minimum work. This relationship is now known asMurray's law and states that the cube of the diameter of a parent vessel(do) equals the sum of the cubes of the diameters of the daughtervessels i.e. d³ ₀=d³ ₁+d³ ₂

d³ ₀=2d³ ₁

Biomimetic design principles could play a significant role is mimickingthe structure of vascular trees (i.e. glomerular tuft) to improve theflow through microfluidic channels and manifolds. The vessels found inmammalian systems are usually arranged in hierarchical structures and adistinctive feature of this arrangement is their multi-stage division orbifurcation. At each generation, the characteristic dimension of thevascular modules will generally become smaller, both in length anddiameter. Similar configurations often occur in microfluidic manifoldswith the inlet channel branching into smaller channels.

A generalized form of Murray's law has been developed that can beapplied to the design of microfluidic channels and manifolds found inlab-on-a-chip systems. Murray's law was originally developed forcardiovascular systems composed of multi-diameter circular pipes and thepresent theory has used this biological principle to designconstant-depth artificial vascular systems composed of rectangular ortrapezoidal cross-sections. Biomimetic principles can now be applied tomicrofluidic devices fabricated using conventional batch processingtechniques. This novel design approach removes the need to fabricatecomplex, multi-depth microstructures which would otherwise requiredifficult multi-exposure and alignment steps.

Murray's law was originally derived from biological considerations andits applicability to microfluidic structures is only just beingrecognized. It has been shown that by carefully selecting the branchingparameter governing each bifurcation; it is possible to introduce aprescribed element of control into the flow behavior. For example,hydrodynamic forces may damage shear-sensitive cells and the ability topredict and control a low-shear environment within the network couldbenefit cell response studies involving free-flowing or anchored cells.

Now this microfluidic technology to generate microvasculature is not aperfect system. After all, different types of microvasculature act morethan just delivering the blood to the tissues and organs. The extensivemicrovasculature is highly involved in many forms of mass transfer whichoccurs across many forms of capillaries. However, these specialproperties will be emulated and achieved using various semipermeablemembranes with different chemical, physical characteristics andporosities. Hence, when microfluidic technology is used in combinationto generate various forms of tissue and organ microvasculatures, theywill emulate many types of microvasculature for various medical devicessuch as specialized dialysis systems, organ/tissue bio-reactors,bio-artificial organ supports and etc.

Microfluidic Capillaries and Lymphatics Technology (MCAL Technology) andits various biomimetically designed microfluidic-based chipsetunits/modules/segments.

In one embodiment, the special design of a group of microvascularconduits (capillaries & lymphatics) is as follows: The channels ofdesired shapes with different aspect ratios (width (W), height (H) andlength (L)) and various designs and topologies are fabricated on themicrofluidic chip utilizing different inert and biocompatible polymersfor microfluidic substrates (PDMS, Photo resin, etc.). In addition,double or multilayered microfluidic chips having either differentdesigns or mirror image of each other will be used to sandwich one ormultiple types of interchangeable semipermeable membranes separatingdifferent layers. It should be noted and emphasized that a permutationof different microfluidic chips with different microchannel structures,shapes and aspect ratios could be used in combination of one or multipledifferent semipermeable membranes (synthetic, semisynthetic,biocompatible, porous, flux and diverse molecular weight cut-offpermeability). This MCAL Technology-core technology-in fact will allowconstruction of various biomimetically designed microfluidic-basedchipset units that act or emulate functions of different capillariesneeded for different applications for improvement of human health.

Ultimately, the double or multilayered combination of the microfluidicchips with different channel designs, aspect ratios and semipermeablemembranes with different chemical, physical characteristics and porositywill produce many varieties of biomimetic structures that are modularand scalable that could be connected in parallel and/or in series! Thepermutation of these chipset units will be used to generate so manydifferent types of artificial organ/tissue microvasculature whichultimately be used for production and manufacturing of various medicaldevices such as specialized dialysis systems, organ bio-reactors,bio-artificial organ supports and etc. that will be used in fields ofmedical therapeutics, diagnostics and bio-engineering.

Microfluidics enables small dimensions of individual micro-channels 110a-d, which significantly decreases the lateral distance to diffusethrough to the exchange semipermeable membrane. As diffusion time scaleswith the square of the distance, shrinking the lateral dimension just 10times speeds up the diffusion by a factor of 100. Faster diffusion meansmore efficient filtration and higher removal percentage even if allother parameters remain the same.

Microfluidics uses photolithography to build very large and densenetworks of micro-channels 110 a-d with essentially the same ease asmaking a single channel. This feature allows for a highly efficientnetwork of parallel small channels to be fabricated at low cost. Thenetwork combines the fast diffusion with a large increase ofsurface-to-volume ratio, as the thin sheet device containing the networkhas the same contact surface area as the traditional device, whilehaving many times smaller volume. This results in a far more efficientdevice. Furthermore, the use of a large number of small channels allowsfor individual channel width to remain small enough to avoid mechanicalcollapse while the channel height is kept very small to allow for fastlateral diffusion. The result is the binary-tree architecture ofmicro-channels 110 a-d as seen in FIG. 8B

It is also necessary to emphasize that multiple types of microfluidicchip units 102 a-d may be used in parallel and/or in series in thepresent invention. The followings are the list of the variousmicrofluidic chipset units that are based on MCAL technology. It shouldbe emphasized that each layer of the MCAL Technology Chipsetunit/segment/module may contain 1. Blood and its components 2.Plasma/Serum and their components 3. Fluids with different compositionsincluding nutrients or other necessary cell/tissue support elements,growth hormone etc. 4. Different components of tissue/organ, combinationof cells, stem cells and other components of organs and tissues 5.Oxygen/air 6. Dialysate and replacement fluids 7. Albumin 8. ActivatedCharcoal 9. Lipids 10. Resin, ion exchange resin.

In designing the various microfluidic chipset modules, the microchannelsmay take any shape, topology and configurations. Hence, any form ofmicrochannel design could be used including but not limited to straight,crisscrossing, fractal, curvilinear channels or interrupted channelsusing pillar design and etc. However, pillar design as opposed to havingcomplete channels is more optimal. The pillar design will allow 1000micro width for each “channel” and provide a larger fill volume for eachchipset. The dimensions of these pillars could range between I 0-50microns however smaller than 20 micron may not release well.

For the purpose of the inflow and outflow design of these variousmicrofluidic chipset modules, a ledged design to control thedistribution hydraulic resistance to be three orders of magnitude lowerthan the forward flow resistance in the permeation region. This meansthat there will be almost no non-uniformity in the pressure laterallyacross the permeation region.

In addition, each and every microfluidic chipset unit/segment/modulethat is manufactured based on the MCAL Technology will have the optionsof integrated heating and cooling elements and the heatsink if neededand are optional.

The most outer layers on each side of the module are heatsinks. The TEConly pumps heat and for cooling the module down, a heatsink is placed todissipate energy. To heat up the module, the heatsinks capture theenergy.

One microfluidic MCAL Technology module may have any or all the 7layers:

For the purpose of the inflow and outflow design of these variousmicrofluidic chipset modules, a ledged design to control thedistribution hydraulic resistance to be three orders of magnitude lowerthan the forward flow resistance in the permeation region. This meansthat there will be almost no non-uniformity in the pressure laterallyacross the permeation region.

In addition, each and every microfluidic chipset unit/segment/modulethat is manufactured based on the MCAL Technology will have the optionsof integrated heating and cooling elements and the heatsink if neededand are optional.

-   -   The heating element is a TEC (Peltier device). The copper plates        are utilized to transfer the heat and cold uniformly to the MCAL        Module. Utilizing the TEC, the various modules have the capacity        to perform at one, elevated temperature, or even generate a        temperature gradient across the chipset/membrane to motivate        faster permeation, diffusion and convection and etc.    -   The most outer layers on each side of the module are heatsinks.        The TEC only pumps heat and for cooling the module down, a        heatsink is placed to dissipate energy. To heat up the module,        the heatsinks capture the energy.    -   One microfluidic MCAL Technology module may have any or all the        7 layers:    -   1. Heatsink    -   2. The Cooper layer    -   3. The TEC (Peltier device)    -   4. The Microfluidic Chipset Unit    -   5. The TEC (Peltier device)    -   6. The Copper Layer    -   7. Heatsink    -   Furthermore, in another design, the heating and cooling could be        built external to the chipset modules as well. Also a couple or        more adjacent modules may share some of the components of        heating cooling system.    -   Another optional feature of these MCAL Modules is the capacity        to have micro-vibration assembled on each modules and/or a group        of modules to have their own dedicated micro vibration unit.

This innovative and proprietary MCAL Technology has the followingbenefits which sets it apart from other. These are the followings:

-   -   Emulating different vasculatures (capillaries, lymphatics)    -   Faster Diffusion & Convection    -   Higher Efficiency    -   Higher Surface Area(SA) to Volume (V) Ratio (SAN)    -   Higher Clearances for Important Uremic Toxins    -   Scalable/From a Smaller Units/modules to a Larger Ones    -   Can be connected in Series or Parallel or in Combination    -   Multilayer with each layer acting either as a lymphatic or        different type of capillary    -   Modular & Adjustable    -   Variable Angled cross flow/Countercurrent Flow    -   Variable aspect ratios ranging from 10 um to 2 mm    -   Can be used in many different applications

This list includes 18 basic units/modules/segments but is not limited toonly these configurations. It should be noted that the microfluidicmodules beyond a 2-layered design may have a combination of many ofthese various semipermeable membranes with wide-ranging chemical,physical characteristics as well as porosities. The Bio-ReactorModule-the BR Module-is just an example of this combination of differentmembranes in a multilayer module design.

1. The HD Chipset (Hemodialysis Function) in formation of this module,any type of high flux or low flux hemodialysis membranes will be used.2. The UF Chipset (Ultrafiltration Function) in formation of this anytype of ultrafiltration membranes will be used.3. The PS Chipset (Plasma Separation/plasmapheresis) in formation ofthis any type of plasmapheresis/plasma separation membranes will beused.4. The HP Chipset (Hemoperfusion) in formation of this any type ofhemoperfusion will be used.5. The AD Chipset (Albumin Dialysis) in formation of this any type ofHMWCO membranes will be used.6. The D Chipset (Diafiltration) in formation of this any type of CRRTmembranes will be used.7. The RDF Chipset (Hemodiafiltration) in formation of this any types ofCRRT membranes will be used.8. The DR Chipset (Dialysis Regeneration) in formation of this acombination of resin, activated charcoal, zirconium etc. will be used.9. The O Chipset (Oxygenation) in formation of this any type of ECMOmembrane will be used.10. The HD Chipset (Hemodialysis/High Efficiency) in formation of thisany type of high efficiency hemodialysis membranes will be used.11. The ADR Chipset (Albumin Dialysis and Regeneration) in formation ofthis combination of any type of HMWCO membranes with a combination ofresin, activated charcoal, zirconium etc. will be used.12. The BR (Bio-Reactor Chipset-Tissue Support using HMWCO Membrane) information of this combinations of any type of ECMO membrane with allother semipermeable membranes including HMWCO membranes in amultilayered modules.13. The RO (the reverse Osmosis) in formation of this any type ofreverse osmosis membranes will be used.14. The FO (Forward Osmosis) in formation of this any type of forwardosmosis membrane will be used.15. The EDI (Electrodeionization) in formation of this any type of ionexchange membranes and resins will be used.16. The ED (Electrodialysis) in formation of this type of ion-exchangemembranes in combination with an applied electric potential difference.Electrodialysis (ED) is used to transport salt ions from one solutionthrough ion-exchange membranes to another solution under the influenceof an applied electric potential difference. This is done in aconfiguration called an electro-dialysis cell.17. The EF (Electrofiltration) in formation of this any type of membranefiltration and electrophoresis process will be used. Electrofiltrationis a method that combines membrane filtration and electrophoresis in adead-end process.18. The LD (Lipid Dialysis) in formation of this any type of membranesto dialyze against any inert and biocompatible lipid solutions will beused.

Each Chipset module is designed to emulate some of the function of humancapillaries or lymphatic (though not exactly and precisely). Each basicchipset module which utilizes a specific or various semipermeablemembranes to allow manipulation of blood, blood components, plasma,water, electrolytes, nitrogenous waste, amino acids, albumin, globulins,hormones and enzymes, nitrogenous waste, nutrients, and gases.

Different Types of Applications for the Microfluidic-based Capillariesand Lymphatic Technology (MCAL Technology) and its variousbiomimetically designed microfluidic-based chipset units mentionedabove.

#1. Combined microfluidic based kidney and Liver dialysis device forMODS and/or Sepsis#2. Mobile, modular and scalable kidney and/or liver dialysis systems#3. Microfluidic based Bio-Reactors for various organ/tissue supportsystems#4. Bio-Artificial organ support systems (combinations of #3 with #1 or#2)#5. Microfluidic based on demand Intravenous Fluid and dialysateGenerator: For generating ultrapure water from tap water for intravenoususe or dialysate use . . . This will allow to generate different typesof i.v. fluids for medical use.

Combined Microfluidic Based Kidney and Liver Dialysis Device for LiverFailure and Multi-Organ Dysfunction Syndrome (MODS) and/or Sepsis

This is the design for a modular and scalable combined kidney and liverdialysis device that is based on the MCAL Technology. This highlyefficient dialysis device will replace the inefficient hollow FiberTechnology currently in clinical use. This device is termed combinedmicrofluidic based kidney and Liver dialysis device using combination ofthe MCAL Technology core technology building-block units a modularmicrofluidic dialysis system can be designed which provides ahemodialysis device to perform both kidney and liver dialysis needed inliver failure and also multiorgan failure in MODS and sepsis.

The currently available dialysis devices essentially only eliminatewater-soluble substances of low or intermediate molecular weight, hencethey are very inefficient.

These standard dialysis based processes do not achieve sufficientremoval of uremic toxins (the middle molecules) as well as the notoriousprotein-bound substances.

In addition, currently, there is no liver dialysis system to provideclearance of tightly bound hepatic toxins accumulated during liverfailure.

Therefore, for acute liver failure or an acute exacerbation of chronicliver failure (acute on chronic liver failure) regular dialysismodalities are not sufficient.

However, in this unique combined microfluidic based kidney and Liverdialysis device a combination of the known dialysis processes(diffusive, convective as well as adsorptive, CRRT, Hemodialysis,hemodiafiltration, hemoperfusion, albumin dialysis and novel and uniquelipid dialysis)) with “special” maneuvers that manipulate the blood,plasma (utilizing plasma separation/plasmapheresis membranestechnology), which will increase the efficiency of standard dialysisplus ultimately increasing the free serum concentration of“protein-bound toxins” could effectively improve the inefficiency ofdialysis for kidney or liver as well as Kidney and Liver. Simply put,this is the basis for the combined microfluidic based kidney and Liverdialysis device.

It is important to note that the fashion that these membranes andfilters are placed together and their permutation are part of thispatent.

The Combined microfluidic-based kidney and Liver dialysis device can bemade in a compact form to be used for many different types ofMulti-System/Multi-Organ Dysfunctions associated with liver and kidneyfailure such as:

Acute on Chronic Liver Failure (ACLF)

ALF (Acute Liver Failure)+AM or CKD

CLF (Chronic Liver Failure)+AM+CKD

AM

Sepsis

MODS

Combined microfluidic based kidney and Liver dialysis device utilizesthe following mechanisms to increase efficiency of kidney dialysis aswell a liver toxin removal:

-   -   Reducing Recirculation (use of two accesses, each in a different        limb, to decrease recirculation entirely)    -   Reducing the blood flow and blood volume required for optimal        dialysis    -   Reducing dead-space (After plasmapheresis mostly the plasma is        occupying the precious membrane surface area that is so crucial        for the more efficient dialysis processes.)    -   Increasing the convective dialysis by increasing        -   a. Ultrafiltration        -   b. Internal filtration    -   Increasing the free serum concentration of the protein-bound        toxins via dilution with Specialized Replacement Fluids to favor        the equilibrium towards higher serum concentration of the        non-bound toxins        -   c. Example. 1:4 dilution and subsequently a 1:4 dilution via            replacement fluids will yield a 1:16 dilution of the free            toxins which will force the change in equilibrium    -   Certain chemicals can change the equilibrium as well as the        temperature    -   Use of albumin for albumin dialysis    -   Use of novel lipid dialysis (optional)    -   Using combination of Albumin with/without Charcoal and Resins        for a specialized albumin based dialysis and specialized        dialysate

This device utilizes a plurality of various microfluidic-based chipsetunits/modules/segments—based on MCAL Technology-that are arranged inmodular configuration for efficient dialysis of blood and dialysate;whereby the microfluidic device comprise of various modules, havingintegrated micro-pumps for continuous pumping of blood and dialysate,micro-valves for determining flow direction of the blood and dialysate,and a plurality of biomimetically designed micro-channels that emulatethe natural microvasculature of the body for optimal flow of blood anddialysate, whereby a microfluidic dialysate regenerating unit/module (DRModule) independently regenerates spent dialysate for use by themicrofluidic units(optional).

Those skilled in the art will recognize that the loss of kidney functionresults in the accumulation of many metabolites, some of which have beenidentified and their toxic effects on cell metabolism elucidated. Thesetoxins fall under the two categories of 1. Middle molecular weighturemic toxins and 2. Small solutes that are highly protein bound and aredifficult to remove from the blood via regular diffusive dialysis. Theseare the protein-bound uremic toxins Over a hundred of such uremic toxinshave been identified, and their removals by various modalities of renaland liver replacement therapy have been studied.

Liver function is regularly divided into two major categories: 1.Synthesis and 2 Toxin removal. The liver synthesizes many of theessential proteins for body function. In addition liver is an activeorgan in metabolism of many toxins and their removal. The only currenttherapy to return the hepatic synthetic function is only livertransplantation. Liver transplantations are performed on less than 25%of patients with acute liver failure because no adequate process fortaking over the detoxification function exists, so the time taken forthe hepatic function to recover cannot be bridged.

Uremic and hepatic toxins are accumulated in a number of diseasesrelated to the kidney and liver diseases respectively. The majordifference between the uremic and hepatic toxins is that majority of thehepatic toxins are protein-bound complexes, hence not easily dialyzable.Therefore, for acute liver failure or an acute exacerbation of chronicliver failure (acute on chronic liver failure) regular dialysismodalities are not sufficient.

Hepatic toxins associated with liver failure vary with respect tomolecular size and physicochemical characteristics. Typically, asignificant proportion of toxins are albumin-bound (e.g. bilirubin, bileacids, and hydrophobic amino and fatty acids). There is growing evidencesuggesting an important role of these toxins in the development andmaintenance of multi-organ failure subsequent to hepatic failure.Another significant proportion of toxins comprise water-soluble toxinsof low- and middle-molecular weight. They are derived either fromhepatic failure (e.g. ammonia), or renal dysfunction and are efficientlyremoved by either hemodialysis or hemofiltration. To date, however,conventional methods failed to remove of albumin-bound toxinseffectively.

Other proposals have involved dialysis systems for the liver dialysiswhich currently is non-existence and for improvement of kidney dialysisadequacy. In addition to limited efficiency, they only provide marginaland partial removal of middle molecular weight toxins Thus, there aregreat unmet needs exist in the industry to address the aforementioneddeficiencies and inadequacies.

The general design of the Combined microfluidic-based kidney and Liverdialysis device is utilizing the MCAL Technology-the various CoreTechnology microfluidic chipset units/modules in different combinationsand permutations. This novel dialysis device will have several differentcomponents comprise of the modular and scalable basic microfluidicchipset units/modules that are connected in parallel and/or in serieseither on or off one or multiple microfluidic chips to design anddevelop the desired devices. It should be noted that in order to improvethe efficiency of this unique microfluidic based dialysis device, thearterial and venous ports are separated and are placed on opposite limbsto decrease the recirculation rate close to zero.

The blood from the patient is pumped through a single lumen catheter(the arterial line of the dialyzer), and then is anticoagulated (ifneeded) before entering the first module of the combined microfluidicbased kidney and Liver dialysis device.

The components of the combined microfluidic-based kidney and Liverdialysis device are as follows:

1. PS module/unit (plasma separation) 2. HD module/unit (Hemodialysis)3. HP module/unit (Hemoperfusion) 4. HDF or DF module/unit(Hemodiafiltration) or (Diafiltration) 5. AD module (Albumin Dialysis)6. ADR module (Optional Regeneration of Albumin Dialysate) 7. DR module(Optional Dialysate regeneration) 8. LD module (Optional Lipid Dialysis)

Note: The device can either initially performs

1. A regular hemodialysis or hemodiafiltration plus replacement fluid onthe whole blood and then perform the plasmapheresis to generate plasmaportion for further manipulation and dialysis.2. Perform a plasmapheresis generate a plasma portion then perform aregular hemodialysis and/or hemodiafiltration etc. on the plasmaportion.The Cellular portion from the plasmapheresis will be returned to patientimmediately or go through a regular dialysis additionally (optional).

The PS Module—This module is designed to emulate some of the function ofa glomerulus in human nephron, (though not exactly and precisely). The Gmodule which utilizes the plasmapheresis membrane will allow plasmaWater, Albumin, Globulins, Amino acids, Hormones and Enzymes,Nitrogenous waste, Nutrients, Gases and Fibrinogen to be filteredTherefore, the PS module will filter all non-cellular components of thewhole blood and generate two portions.

One portion is the portion containing mostly the cellular elements ofthe blood (WBCs, RBCs and Platelets) and some plasma. This is calledCell Portion (CP).

The other portion is the portion containing non-cellular components ofthe whole blood (all proteins, electrolytes, and albumin). This iscalled the plasma portion (PP).

The CP will be directed back to the patient (BTP), while the PP portionenters the next module of the dialysis apparatus to be dialyzed andcleaned.

The HD module—This module is designed to emulate partial clearance ofglomerulus and tubules.

The PP will be diluted 1:1 to 1:4 ratios by an isotonic replacementfluid (RF) using a reservoir that contains fresh unused RF. This 1:1 to1:4 (Plasma: RF) dilutions drastically reduces the albumin and proteinconcentration of the PP hence increasing the free plasma portion ofprotein and albumin-bound toxins. In addition the dilution reduces therisk of coagulation and hence the need for anticoagulation.

The HDF Module—This module is designed to emulate the filtrationfunction of the glomerulus in the human nephron. The diluted PP entersthe HDF module which utilizes hemodiafiltration membrane and undergoes agood diffusive and convective dialysis in addition to an intensiveinternal filtration due to increased length of the fiber/channel as wellas decreased diameter of the fiber/channel. Of course a dialysate isused during this process which will be regenerated through the DRmodule. The PP which is well dialyzed is directed to the next module ofthe dialysis device. (Option/to save dialysate using the back filtrationwe regenerated some due to reduced filtration).

The HP Module—This module is designed to imitate the function of thetubule portion of human nephron. The well dialyzed PP now enters the HPmodule which utilizes a hemoperfusion procedure using a suspension ofcharcoal and resin. PP will be hemoperfused against the fresh resin andcharcoal. The PP is further cleared from protein-bound toxins. The PP isagain diluted I: to I:4 using fresh isotonic replacement fluid beforeentering the next module.

The AD Module—This module is designed to imitate another function of thetubule portion of the human nephron. The PP enters the AD module whichutilizes a high performance membrane with very High-Molecular-WeightCut-Off (HMWCO) characteristic to perform an Albumin Dialysis. The PPwill be dialyzed against a reservoir of fresh albumin or a combinationof albumin plus charcoal/resin. This reservoir will be regenerated toremove the captured protein-bound toxins and avoid saturation of albuminbinding. The PP is returned via a separate line using a single lumencatheter to the patient via the opposite limb as explained above.

The DR Module—This module is designed to regenerate the spent dialysateusing a reservoir of charcoal and resin. The spent dialysis is runthrough the suspension of charcoal and resin and other substances toregenerate the dialysate. The regenerated dialysate is returned to therequired modules as needed. Option: this regeneration can be eliminatedand dialysate fresh can be used without regenerating it.

The ADR module-this module is designed to regenerate the spent albumin.

The MCAL Technology module ADR (Albumin Dialysis Regeneration)

A multilayered PDMS based Microfluidic Chipset for more efficientalbumin dialysis.

A multilayered PDMS microfluidic chipset is designed for performing muchmore efficient albumin dialysis and removal of the protein/albumin-boundtoxins. This chip design is unique since the albumin regeneration isbuilt on the chip.

A multilayered PDMS based microfluidic chipset. At least a single layerof PDMS for blood compartment (blood layer) sandwiched between twotwo-layered charcoal and albumin dialysate layers placed in mirror imageas described below:

1. 1^(st) layer . . . Dialysate with charcoal Flow →→→ 2. 2^(nd) layer .. . Dialysate with albumin Flow  

3. 3^(rd) layer . . . Plasma Portion (P.P.) Flow →→→ from plasmapheresis4. 4^(th) layer . . . Dialysate with albumin Flow  

5. 5^(th) layer . . . Dialysate with charcoal Flow →→→

Between each of the following layers, the 1^(st) & 2^(nd), 2^(nd) &3^(rd), 3^(rd) & 4^(th) and 4^(th) & 5^(th) layers, a high flux membrane(or other semipermeable membranes) will be placed to separate each layercompartment and provide the surface for dialysis to occur.

Note: All fluids flow in a countercurrent direction respect to theiradjacent layers

1. 1^(st) layer . . . Dialysate with charcoal Depth of channels 20-200um2. 2^(nd) layer . . . Dialysate with albumin Depth of channels 20-200um3. 3^(rd) layer . . . Plasma Portion (P.P.) Depth of channels 20-100umfrom plasmapheresis 4. 4^(th) (same as 2^(nd) layer) . . . DialysateDepth of channels 20-200um with albumin 5. 5^(th) (same as 1^(st) layer). . . Dialysate Depth of channels 20-200um with charcoal

The concurrent, countercurrent as well as tangential cross flows may beused for best and optimal efficiency

The membranes used can vary but high flux or even membranes with higherMWCO characteristics may be utilized. In addition the rate of flow foreach layer will be studied and optimized.

The diluted and well dialyzed PP enters this module-the A module whichemulates the function of the tubule portion of the human nephron. Thediluted PP enters the A module where Albumin dialysis is performed usingHigh-Molecular-Weight Cut-off (HMWCO) membrane/High Performance Membranewhich allows the PP to be dialyzed against albumin or a combination ofalbumin plus charcoal/resin. The first output of the MCAL Technology-thePP portion-will be directed back to the patient/subject while the secondoutput of this module-the spent albumin dialysate-will be directed tothe module DR for regeneration.

The RO Module—This module is designed to emulate the function of thecollecting tubule portion of the human nephron. The spent dialysate plusultrafiltration will enter the RO module which utilizes a reverseosmosis membrane to extract the water and the rest is discarded as urinelike material. The water is then used for other functions in the device.

The present invention is directed to a modular and scalable microfluidicunit that each that utilizes different and various principles ofmicrofluidics for performing different processes on blood and plasma.These processes includes but not limited to filtration, ultrafiltration,diafiltration, various forms of dialysis, hemoperfusion, plasmaseparation and etc. of any fluid, such as blood, plasma and lymph. Themodular microfluidic dialysis system provides a portable, wearablehemodialysis device that helps remove middle molecular weight uremictoxins, small solutes, hepatic toxins, water, and other impurities fromthe blood through the use of microfluidic technology. The microfluidicdialysis system provides particular advantages in blood dialysis formobile kidney augmentation devices, liver treatment, and fabrication ofan artificial kidney.

In one embodiment, the system utilizes various micro-components thatemulate the physiological parameters of the body. These micro-componentsprovide numerous advantageous over traditional dialysis, such as hollowtube filtration and reverse osmosis. In this manner, the middlemolecular weight uremic toxins and small solutes may be filtered out ofthe blood more efficiently. Furthermore, the system is modular, so as toenable scalability and conformance to different body types andrequirements.

In some embodiments, the system may utilize a portable, lightweight, andwearable hemodialysis device. The device is battery operated. The deviceutilizes tubing to connect to the patient and to a disposable cassettethat contains the means for processing the blood and dialysate. A simpleuser interface enables operation of the device and monitoring of bloodtemperature and pressure. A data transmission portion, such as a Wi-Fitransmitter, enables real time monitoring of physiological parameters ofthe body and mechanical parameters of the system.

In one aspect, a modular microfluidic dialysis system, comprises:

-   -   a plurality of microfluidic units, the plurality of microfluidic        units configured to enable any one of different forms of blood        filtration, ultrafiltration, diafiltration, plasma separation        and dialysis of blood, the plurality of microfluidic basic        building block units can be arranged in modular configuration in        parallel or in series for enabling scalability, the plurality of        microfluidic units at least partially fabricated from inert and        biocompatible polymers commonly used in microfluidic such as a        polymeric organosilicon compound, the plurality of microfluidic        units comprising:        -   a blood microfluidic chip and a dialysate microfluidic chip,            the blood microfluidic chip configured to carry blood, the            dialysate microfluidic chip configured to carry a dialysate,        -   the blood microfluidic chip and the dialysate microfluidic            chip comprising a plurality of micro-pumps, the plurality of            micro-pumps configured to pump the blood to and from the            blood microfluidic chip, the plurality of micro-pumps            further configured to pump the dialysate to and from the            dialysate microfluidic chip,        -   the blood microfluidic chip and the dialysate microfluidic            chip further comprising a plurality of micro-valves, the            plurality of micro-valves configured to regulate the flow of            the blood and the dialysate,        -   the blood microfluidic chip and the dialysate microfluidic            chip further comprising        -   a plurality of micro-channels, the plurality of            micro-channels configured to carry the blood to and from the            blood microfluidic chip, the plurality of micro-channels            further configured to carry the dialysate to and from the            dialysate microfluidic chip, the plurality of micro-channels            defined by multiple widths and topographies; and        -   a semipermeable membrane, the semipermeable membrane            disposed between the blood microfluidic chip and the            dialysate microfluidic chip, the semipermeable membrane            configured to form a permeable barrier between the blood and            the dialysate, the semipermeable membrane further configured            to enable passage of toxins and water from the blood in the            blood microfluidic chip to the dialysate in the dialysate            microfluidic chip; and        -   a microfluidic regenerating unit, the microfluidic            regenerating unit configured to at least partially filter            contaminated dialysate received from the dialysate            microfluidic chip, the microfluidic regenerating unit            further configured to return regenerated dialysate to the            dialysate microfluidic chip.

In a second aspect, the polymeric organosilicon compound is PDMS.

In another aspect, the plurality of micro-pumps comprises electricmicro-pumps and pneumatic micro-pumps.

In another aspect, the plurality of micro-pumps comprises two bloodmicro-pumps, a heparin micro-pump, an ultrafiltration micro-pump, and adialysate micro-pump.

In yet another aspect, the plurality of micro-channels have a wideinlet, a narrow median region, and a narrow outlet.

In yet another aspect, the plurality of micro-channels has a wide inlet,a narrow median region, and a wide outlet or a combination of thesecharacteristics.

In yet another aspect, the plurality of micro-channels is configured insubstantially the same or different topography and width as amicrovasculature of the body.

In yet another aspect, the plurality of micro-channels have a wideraging width of about 100-2000 microns, a depth of about between JO to100 microns, and a length of about between I to 20 centimeters.

In yet another aspect, the topography of the plurality of micro-channelsincludes at least one member selected from the group consisting of:straight, parallel, crisscross, fractal pattern, loops, and branched.

In yet another aspect, the dialysate is an ultrapure dialysate

In yet another aspect, the microfluidic regenerating unit includes atleast one member selected from the group consisting of: a sedimentfilter, a carbon filter, a zirconium carbonate filter, a deionizingresin, a micro-filter, an ultraviolet light, 0.22 micron filter, and acold plasma regeneration apparatus.

In yet another aspect, the microfluidic regenerating unit is configuredto regenerate between 300 milliliters to 1500 milliliters of dialysate.

In yet another aspect, the microfluidic dialysis regenerating unitcomprises a slot, the slot configured to receive a vial of thedialysate.

In yet another aspect, the microfluidic regenerating unit comprisesdimensions of about 20 centimeters in length by 10 centimeters in widthby 10 centimeters in height.

In yet another aspect, the system further comprises one or severalwarming devices, the warming device configured to activate charcoal andother optional sections.

In yet another aspect, the system further comprises one or more coolingdevices.

In yet another aspect, the system further comprises a data transmissionportion, the data transmission portion configured to enable real timemonitoring of physiological parameters of the body and mechanicalparameters of the system.

In yet another aspect, the data transmission portion comprises a Wi-Fitransmitter.

In yet another aspect, the modular configuration of the system isconfigured such that about I 0-100 microfluidic units form amicrofluidic construct.

In yet another aspect, the modular configuration of the system isconfigured such that about 5-20 microfluidic constructs form amicrofluidic module.

In yet another aspect, the microfluidic module positions insidemicrofluidic housing

In yet another aspect, the plurality of micro-valves are configured toclose if the microfluidic module is not disposed in an operableorientation inside the microfluidic housing.

In one embodiment, the device comprises a plurality of microfluidicunits that receive, filter, and return the blood and dialysate to thebody and dialysate reservoir, respectively. The microfluidic units arearranged in modular configuration for enhanced scalability, such thatthe microfluidic units can be added, removed, or rearranged to conformto the dialysis needs of the patient. This allows for more efficientdialysis of the blood.

The multilayered microfluidic units comprise one or multiple bloodmicrofluidic chips, two or more dialysate microfluidic chips, and one ormore semipermeable membranes having different characteristics disposedbetween the chips. The two or more chips (membranes, filters, etc) havesubstantially the same configuration, i.e., mirror images of each other,though various configurations can be used as needed. In one embodiment,all the blood microfluidic chips and all the dialysate microfluidicchips comprise integrated micro-pumps for pumping blood and dialysatecontinuously. This minimizes the need for excessive quantities ofdialysate. The chips further comprise micro-valves for determining flowdirection. The micro-valves remain closed if the chips are not properlyaligned.

The chips further comprise a plurality of micro-channels for carryingthe blood and dialysate to the appropriate chip. The micro-channels areconfigured to emulate the natural microvasculature of the body, i.e.,capillaries, arterioles, venules and lymphatics. In one embodiment, themicro-channels include a narrow channel having different topologies andwidths for optimal flow of blood and dialysate. This uniqueconfiguration of the micro-channels creates fluid shear rates that areamenable to red blood cells contained in blood. The micro-channels havesubstantially smaller diameters than the current hollow fibertechnology; thereby enabling more efficient diffusive and convectivefluid flow.

The micro-pumps, micro-valves, and micro-channels are fabricateddirectly on the respective chip. The micro-pumps, micro-valves, andmicro-channels are also fabricated from inert and biocompatible polymerslike a polymeric organosilicon compound, such as PolyDiMethylSiloxane(PDMS). Those skilled in the art will recognize that PDMS providesnumerous advantageous for microfluidics, including: unique rheologicalproperties for enhanced blood and dialysate flow, transparency forviewing the blood and dialysate, deformability for forming desiredmicro-channel configurations, sticking properties for adhering to otherPDMS components, and non-toxicity.

The blood microfluidic chip and the dialysate microfluidic chip sandwicha semipermeable membrane that provides the filtering capacity for thedialysis. The semipermeable membrane is configured to form a permeablebarrier between the blood and the dialysate. In this manner, thesemipermeable membrane enables passage of toxins, water, and smallelectrolytes from the blood in the blood microfluidic chip to thedialysate in the dialysate microfluidic chip. In one embodiment, thesemipermeable membrane allows only water and small electrolytes to pass.

The device further includes a microfluidic dialysis regenerating unitthat independently regenerates spent dialysate for use by the dialysatemicrofluidic chip. By regenerating the dialysate, a minimal amount ofdialysate is required for operation of the device. In one exemplary use,the microfluidic regenerating unit is configured to regenerate between300 milliliters to 1500 milliliters of the dialysate.

The microfluidic dialysis regenerating unit utilizes various sedimentfilters, carbon filters, deionizing resin, micro-filters, and optionalultraviolet lights and/or cold plasma technology for sterilization and0.22-micron filter to generate an ultrapure dialysate regeneration unit(Optional). The microfluidic dialysis regenerating unit negates the needfor reverse osmosis filtering techniques. The microfluidic dialysisregenerating unit further comprises a slot for receiving a vial ofdialysate. In one embodiment, a plurality of microfluidic dialysisregenerating units fit into a regenerating unit housing.

In some embodiments, the system is modular to enable scalability,adjustability and adaptability for accommodating different types ofpatients with various sizes, accumulated toxin types in the blood(hepatic vs. uremic toxins), medical conditions, support requirement anddialysate requirements. The two or multilayered blood microfluidicchip(s), the dialysate microfluidic chip(s), and the semipermeablemembrane(s) sandwiched there between forms various microfluidic units.About 10-100 microfluidic units form a microfluidic construct. About5-20 microfluidic constructs form a microfluidic module. Themicrofluidic module positions inside a microfluidic housing. In oneembodiment, the microfluidic module must be aligned properly inside themicrofluidic housing before the micro-valves open.

One objective of the present invention is to utilize MCAL technologybasic building blocks and micro-channels having microvasculaturecharacteristics for performing dialysis.

Another objective is to provide a hemodialysis device that is portable,wearable, light-weight and easy to use, and patient friendly.

Another objective is to provide a microfluidic-based dialysis systemthat removes middle molecular weight uremic toxins, small solutes and/orprotein-bound toxins.

Another objective is to regulate extracellular fluid volume and bloodpressure control, electrolyte, acid base control, and correction ofanemia.

Yet another objective is to fabricate the micro-channels from apolymeric organosilicon compound, such as PDMS, that has uniquerheological properties that enhance flow of blood and dialysate, istransparent, sticks to other micro-channels and the respective chip, isdeformable, and nontoxic.

Yet another objective is to create a scalable configuration that enablesadding, removing, and rearranging microfluidic modules from themicrofluidic housing.

Yet another objective is to provide a microfluidic regenerating unit toreplace reverse osmosis functions and components.

Yet another objective is to incorporate the microfluidic housing and theregenerating unit housing in a disposable cassette.

Yet another objective is to enable real time monitoring of thephysiological aspects of the blood and body parts, and the mechanicalcomponents of the system.

Yet another objective is to provide a dialysis system that can operatecontinuously or intermittently, operating from 2-24 hours/day seven daysa week.

Yet another objective is to enable gentle ultrafiltration to avoidsevere post-dialysis fatigue and fluid shifts seen by regular dialysismethods.

Yet another objective is to regenerate dialysate fluid to minimize theamount of dialysate used daily to as little as 300 ml/day to 1500ml/day.

Yet another objective is to provide cost effective dialysis fortreatment of liver and/or kidney failures.

Other systems, devices, methods, features, and advantages will be orbecome apparent to one with skill in the art upon examination of thefollowing drawings and detailed description. It is intended that allsuch additional systems, methods, features, and advantages be includedwithin this description, be within the scope of the present disclosure,and be protected by the accompanying claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described, by way of example, with referenceto the accompanying drawings, in which:

FIG. 1 illustrates a perspective view of an exemplary modularmicrofluidic dialysis system, in an expanded position, in accordancewith an embodiment of the present invention;

FIG. 2 illustrates a perspective view of a modular microfluidic dialysissystem, in a compressed position, in accordance with an embodiment ofthe present invention;

FIG. 3 illustrates a close up view of a modular microfluidic dialysissystem, in an expanded position, in accordance with an embodiment of thepresent invention;

FIGS. 4A and 4B illustrate sectioned side views of an exemplarymicrofluidic unit, where FIG. 4A illustrates a blood microfluidic chip,a semipermeable membrane, and a dialysate microfluidic chip separated,and FIG. 4B illustrates the fully operational microfluidic unit, inaccordance with an embodiment of the present invention;

FIGS. 5A and 5B illustrate perspective views of an exemplarysemipermeable membrane, in accordance with an embodiment of the presentinvention;

FIG. 6 illustrates a sectioned view of multiple layers of asemipermeable membrane positioned on a blood microfluidic chip, inaccordance with an embodiment of the present invention;

FIG. 7 illustrates a perspective view of multiple microfluidic units ina microfluidic housing, in accordance with an embodiment of the presentinvention;

FIGS. 8A and 8B illustrate schematics of exemplary micro-channels, whereFIG. 8A illustrates sectioned side view of a plurality of micro-channelsin a microfluidic unit, and FIG. 8B illustrates microfluidic manifoldswith the inlet micro-channel branching into smaller micro-channels, inaccordance with an embodiment of the present invention;

FIGS. 9A and 9B illustrate a comparison between an HFT dialyzer and anMFC Technology dialyzer, in accordance with an embodiment of the presentinvention;

FIG. 10 illustrates a comparison Table 162 that differentiates theHollow Fiber Technology and MFC technology, in accordance with anembodiment of the present invention;

FIGS. 11A and 11B illustrate perspective top angle views ofmicro-channels fabricated directly on a blood microfluidic chip, whereFIG. 11A illustrates the micro-channels, and FIG. 7 illustratesdialysate flowing through the micro-channels, in accordance with anembodiment of the present invention;

FIGS. 12A, 12B, and 12C illustrate top views of an micro-channelsfabricated directly on a blood microfluidic chip, where FIG. 12Aillustrates straight micro-channels, FIG. 12B illustrates parallelmicro-channels about one hundred microns wide, and FIG. 12C illustratesbranched micro-channels, as used in a bio-artificial liver, inaccordance with an embodiment of the present invention;

FIG. 13 illustrates a sectioned view of an exemplary microfluidicregenerating unit, in accordance with an embodiment of the presentinvention;

FIG. 14 illustrates a perspective view of a plurality of microfluidicregenerating units fitted inside a microfluidic regenerating housing, inaccordance with an embodiment of the present invention;

FIG. 15 illustrates a diagram of an exemplary microfluidic dialysissystem, in accordance with an embodiment of the present invention;

FIG. 16 illustrates atop view of an exemplary bio-artificial liver withbranched micro-channels, in accordance with an embodiment of the presentinvention; and

FIG. 17 illustrates a diagram of an exemplary artificial kidney dialysissystem, in accordance with an embodiment of the present invention

Like reference numerals refer to like parts throughout the various viewsof the drawings.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is merely exemplary in nature and isnot intended to limit the described embodiments or the application anduses of the described embodiments. As used herein, the word “exemplary”or “illustrative” means “serving as an example, instance, orillustration.” Any implementation described herein as “exemplary” or“illustrative” is not necessarily to be construed as preferred oradvantageous over other implementations. All of the implementationsdescribed below are exemplary implementations provided to enable personsskilled in the art to make or use the embodiments of the disclosure andare not intended to limit the scope of the disclosure, which is definedby the claims. For purposes of description herein, the terms “first,”“second,” “left,” “rear,” “right,” “front,” “vertical,” “horizontal,”and derivatives thereof shall relate to the invention as oriented inFIG. 1. Furthermore, there is no intention to be bound by any expressedor implied theory presented in the preceding technical field,background, brief summary or the following detailed description. It isalso to be understood that the specific devices and processesillustrated in the attached drawings, and described in the followingspecification, are simply exemplary embodiments of the inventiveconcepts defined in the appended claims. Hence, specific dimensions andother physical characteristics relating to the embodiments disclosedherein are not to be considered as limiting, unless the claims expresslystate otherwise.

At the outset, it should be clearly understood that like referencenumerals are intended to identify the same structural elements,portions, or surfaces consistently throughout the several drawingfigures, as may be further described or explained by the entire writtenspecification of which this detailed description is an integral part.The drawings are intended to be read together with the specification andare to be construed as a portion of the entire “written description” ofthis invention as required by 35 U.S.C. § 112.

Combined Microfluidic-Based Kidney and Liver Dialysis Device for MODSand/or Sepsis

In one embodiment of the present invention presented in FIGS. 1-17, amodular microfluidic dialysis system 100 provides a portable, wearablehemodialysis device that helps remove middle molecular weight uremictoxins and small solutes, hepatic toxins, water, and other impuritiesfrom the blood 134 through the use of microfluidic technology. Themodular microfluidic dialysis system 100, hereafter, “system 100”utilizes principles of microfluidics for filtering a fluid, such asblood 134 and lymph. The system 100 provides particular advantages inblood 134 dialysis for mobile kidney augmentation devices, livertreatment, and fabrication of an artificial kidney.

As referenced in FIGS. 1-3, the system 100 utilizes variousmicro-components that emulate the physiological parameters of the body132 for enhancing the dialysis process. These micro-components providenumerous advantageous over traditional dialysis, such as hollow tubefiltration and reverse osmosis. Through use of the microfluidic dialysissystem 100, the more difficult to filter middle molecular weight uremictoxins and small solutes may be filtered out of the blood 134 moreefficiently. Furthermore, the system 100 is modular, so as to enablescalability and conformance to different body types and dialysisrequirements.

Looking now at FIGS. 4A and 4B, the device comprises a plurality ofmicrofluidic units 102 a-d that receive, filter, and return the blood134 and dialysate 116 to the body 132. The microfluidic units 102 a-dare chiefly configured to perform dialysis of blood 134 for removingmiddle molecular weight uremic toxins and protein-bound toxins, smallsolutes, hepatic toxins, water, and other impurities from the blood 134through the use of microfluidic technology.

In some embodiments, the microfluidic units/modules 102 a-d are at leastpartially fabricated from a polymeric organosilicon compound. FIG. 6illustrates the microfluidic units 102 a-d fabricated from any inert andbiocompatible polymer used as microfluidic substrate like polymericorganosilicon compound, such as PDMS. The PDMs provides numerousadvantageous, such as unique rheological properties that enhance flow ofblood 134 and dialysate 116, transparency, capacity to stick to othermicro-channels 110 a-d, deformability, and nontoxicity. Though in otherembodiments, various medical grade materials could also be used forfabrication of the microfluidic units/modules 102 a-d.

As illustrated in FIG. 7, the plurality of microfluidic units 102 a-dare arranged in modular configuration for enhanced scalability. In oneembodiment, the microfluidic units 102 a-d are combined into constructsand modules to operatively fit into a microfluidic housing 114. Thenumber, size, and types of microfluidic units/modules 102 a-d can beadapted for meeting various body types and dialysis requirements. Thisallows for more efficient dialysis of the blood 134.

In one example of the modular scalability of the system 100, about 20-40microfluidic units 102 a-d form a microfluidic construct. About 5microfluidic constructs form a microfluidic module. The microfluidicmodule positions inside a microfluidic housing 114. In one embodiment,the microfluidic module must be aligned properly inside the microfluidichousing 114 before the micro-valves open. This helps minimizeinefficient functioning of the system 100.

Looking back at FIG. 1, each the microfluidic unit comprises a bloodmicrofluidic chip 104, a dialysate microfluidic chip 106, and asemipermeable membrane 108 disposed between the chips 104, 106. Theblood microfluidic chip 104 is configured to carry blood 134, while thedialysate microfluidic chip 106 is configured to carry a dialysate 116.Both chips have substantially the same configuration, i.e., mirrorimages of each other. In one embodiment, different layers of themicrofluidic chipset 104,106 are substantially flat substrates that forma width of about 100-1000 microns. This 100-1000 micron width mayinclude the width of the semipermeable membrane 108. FIG. 2 shows thechips 104, 106 facing each other with the semipermeable membrane 108sandwiched there between.

Looking back at FIGS. 5A and 5B, the blood microfluidic chip 104 and thedialysate microfluidic chip 106 are separated by a semipermeablemembrane 108. The semipermeable membrane 108 provides the filteringcapacity for the dialysis. As FIG. 2 illustrates, the semipermeablemembrane 108 is configured to form a permeable barrier between the blood134 and the dialysate 116. In this manner, the semipermeable membrane108 enables passage of toxins, water, and small electrolytes from theblood 134 in the blood microfluidic chip 104 to the dialysate 116 in thedialysate microfluidic chip 106.

In one embodiment, the semipermeable membrane 108 allows only water andsmall electrolytes to pass. In another embodiment, the semipermeablemembrane 108 is multilayered and comprises: a first layer 112 a ofactivated charcoal; a second layer of resins 112 b; a third layer 112 cof specialized resin zirconium; and a fourth layer 112 d of uremic.Though other filtering substrates and materials may also be used.

In one embodiment, the blood microfluidic chip 104 and a dialysatemicrofluidic chip 106 comprise integrated micro-pumps 130 a-c forpumping blood 134 and dialysate 116 continuously. Though the micro-pumps130 a-c may also pump blood 134 or dialysate 116 intermittently, asneeded. The micro-pumps 130 a-b are configured to pump the blood 134 toand from the blood microfluidic chip 104. Similarly, the micro-pumps 130c are configured to pump the dialysate 116 to and from the dialysatemicrofluidic chip 106. The miniature size of the micro-pumps 130 a-cminimizes the need for excessive quantities of dialysate 116 to be usedfor dialysis, which enhances portability and weight considerations forthe system 100.

In one embodiment, the micro-pumps 130 a-c may be specialized to pumpspecific fluids. For example, the micro-pumps 130 a-c may include: twoor more blood 134 micro-pumps 130 a-c, one or more heparin micro-pump,one or more ultrafiltration micro-pump, and one or more dialysate andreplacement fluid 116 micro-pump. In one embodiment, the plurality ofmicro-pumps 130 a-c may include either electric micro-pumps 130 a-c orpneumatic micro-pumps 130 a-c.

The electric micro-pumps 130 a-c are powered by the battery in themicrofluidic unit The pneumatic pump may include a manual balloon handmicro-pump that can be used to generate and store a pressurizedatmospheric air in a special reservoir for storage of compressed air ina Compressed Air Reservoir (CAR). This pressurized air operates thepneumatic micro-pumps 130 a-c to lower use of battery power. Inaddition, the manual balloon hand micro-pump can be used manually toregenerate power.

In some embodiments, the chips further comprise micro-valves 154 a-c fordetermining flow direction and mode of movement for the blood 134 andthe dialysate 116 (FIG. 15). The micro-valves 154 a-c remain closed ifthe chips are not properly aligned. The micro-valves 154 a-c may becontrolled remotely or manually preset to a desired position. Factorssuch as pressure and the type of dialysate 116 also dictate the positionof the micro-valves 1 54 a-c. In one embodiment, an inflow and outflowtubing is attached to a manifold for dividing the blood 134 anddialysate 116 to each microfluidic chip 104, 106 and its associatedmicrofluidic unit 102 a-d.

The chips 104, 106 further comprise a plurality of micro-channels 110a-d for carrying the blood 134 and dialysate 116 to the appropriate chip104, 106. As shown in FIG. 11A, the micro-channels 110 a-b may befabricated directly on the blood microfluidic chip 104 to carry theblood 134 to and from the blood microfluidic chip 104. In one example,FIGS. 12A, 12B, and 12C illustrate top views of micro-channelsfabricated directly on a blood microfluidic chip, where FIG. 12Aillustrates straight micro-channels, FIG. 12B illustrates parallelmicro-channels about one hundred microns wide, and FIG. 12C illustratesbranched micro-channels, as used in a bio-artificial liver.

As illustrated in FIGS. 11A and 11B, the microfluidic chips are designedwith the following variables:

-   -   Shape of the Channels: These microfluidic channels are designed        in linear, parallel, crisscrossing, pillars and fractal or a        combination of these shapes.    -   Size of the Channels: These microfluidic channels have different        dimension with different aspect ratios.    -   Semipermeable Membrane types: These microfluidic channels are        covered with different semipermeable membranes with different        porosity (pore size), various Molecular Weight Cut Off (MWCO)        values and different membrane characteristics to create        specialized biomimetic vasculature-capillaries and lymphatic.    -   Number of Layers: These chipsets can be double layer ton-layers        as needed.    -   Types of Resin or Polymer Used: inert, biocompatible polymers        such as PDMS, Photo resin etc.    -   The angled Countercurrent: The angle of the flow in the        dialysate channels vs. the flow in other layers could range from        0 degrees (same direction/co-current flow) to 180 degrees        (counter-current flow). This range of angled counter-current        flow has advantages of providing a uniform gradient across the        microfluidic chipset. Optimization for each Chipset can be done.        In addition since the channels for the dialysate will be in the        shape of “broken channels walls” or use of interrupted pillars,        the flow of the dialysate has always three options: 0 degrees,        90 degrees and 180 degrees (see sketch)    -   Use of Enhanced Dialysate: Standard dialysate will be used to        make different concentrations of an activated mesoporous        charcoal solution to increase the clearance while avoiding        plugging of the channels.

Thus, FIG. 8A illustrates one single micro-capillary unit made from twoPDMS micro-channels 110 a-d which sandwich a semipermeable dialysismembrane. This unit now emulates a capillary in the human body. Bychanging the characteristics and permeability of the membrane one canachieve different types of capillaries for engineered tissue and organ.The core technology described here is based on a combination of themicrofluidic technology which can provide a very narrow conduit from 10um to as large as 10000 microns width “conduit” or “channel” ofdifferent topology and shapes. This will allow emulating themicrovasculature. However, this basically can act as a fluidtransporter. However when this technology is combined in a particularmanner, a non-biological representation of different capillaries andlymphatics is achieved. This core technology will be used to generatedifferent tissues and/or organs to improve human health by eithersupporting or replacing the failing organs.

This innovative and proprietary MCAL Technology has the followingbenefits which sets it apart from other. These are the followings:

-   -   Emulating different vasculatures (capillaries, lymphatics)    -   Faster Diffusion & Convection    -   Higher Efficiency    -   Higher Surface Area(SA) to Volume (V) Ratio (SA/V)    -   Higher Clearances for Important Uremic Toxins    -   Scalable/From a Smaller Units/modules to a Larger Ones    -   Can be connected in Series or Parallel or in Combination    -   Multilayer with each layer acting either as a lymphatic or        different type of capillary    -   Modular & Adjustable    -   Variable Angled cross flow/Countercurrent Flow    -   Variable aspect ratios ranging from 10 um to 2 mm    -   Can be used in many different applications

Furthermore, microfluidics enables small dimensions of individualchannels, which significantly decreases the lateral distance to diffusethrough to the exchange membrane. As diffusion time scales with thesquare of the distance, shrinking the lateral dimension by 10× speeds upthe diffusion by 100×. Faster diffusion means more efficient filtrationand higher removal percentage even if all other parameters remain thesame. This characteristic alone can improve the efficiency of dialysis50-100 folds.

Furthermore, microfluidics uses photolithography to build very large anddense networks of channels with essentially the same ease as making asingle channel The network combines the faster diffusion with a largeincrease of surface-to-volume ratio, since the microfluidic device hasthe same contact surface area as the traditional device, while havingmany times smaller volume.

The microfluidic system 100 allows for stacking many identical layersthat are connected in parallel. Stacking preserves the superiorsurface-to-volume ratio while increasing the overall surface area of theexchange membrane as well as the volumetric throughput of the device, bya factor equal to the number of stacks. If the footprint of the deviceis allowed to increase as well, the parallel microfluidic connectingmakes that factor scale like the cube of the linear dimension of thedevice! Hence, a 10× increase in the linear dimension would result in a1,000× increase in membrane surface area and in volumetric throughput.Thus, the proposed system would have significantly improved removal rateof toxins compared to traditional dialysis modalities.

By utilizing different specialized membranes such as Hemodiafiltration(RDF), HMWCO membranes the microfluidic device combines diffusive andconvective transport to increase the clearance of middle-to-largemolecules. Online hemodiafiltration (OL-RDF) has allowed the convectivevolume to be increased and has reduced the cost of the procedure.Studies have shown that OL-RDF reduces the incidence of amyloidosis andchronic inflammation, and decreases the mortality risk.

These microfluidic chipset modules can be stacked (i.e. Stacking 10, 20,etc. identical prototypes vertically and connecting them in parallel) toachieve scalability This special feature would allow gain of many foldsin throughput. Thus, this device would have 4× the volumetricthroughput, while offering higher efficiency of toxin removal by fasterdiffusion. The result would be significantly better therapy in afraction of the traditional duration.

FIGS. 9A and 9B illustrate a comparison between an RFT dialyzer 158 andan MFC Technology dialyzer 160, while keeping the volume the same.

The micro-channels 110 c-d follow a top down approach: The inflow intothe chipset module is via a central inlet (or other approaches) which isdivided in successive steps to provide a network of micro-channels 110a-d to distribute the oxygen, fluids and nutrients in a coordinated anduniform pattern. The inlet and outlet will have several design includinga ledged design to control the distribution hydraulic resistance to bethree orders of magnitude lower than the forward flow resistance in thepermeation region. This means that there will be almost nonon-uniformity in the pressure laterally across the permeation region.

In some embodiments, the microfluidic regenerating unit 118 a-c mayinclude at least one filtering/purifying member selected from the groupconsisting of: a sediment filter, a carbon filter, a zirconium carbonatefilter, a deionizing resin, a micro-filter, an ultraviolet light, and acold plasma regeneration apparatus. The microfluidic dialysisregenerating unit 118 a-c negates the need for reverse osmosis filteringtechniques. Though, as shown in FIG. 15, forward dialysis and reverseosmosis may still be used in the system 100.

In yet another embodiment, the filtering components of the microfluidicregenerating unit 118 a-c may include: a) Activated Charcoal (1 gram=500m² surface area); b) Urease(NH2CO+H20→CO2+2 NH3; c) Zirconium Phosphate;d) Zirconium Oxide plus Zirconium carbonate; e) Composite Dry Chemical(to mix in with K, Mg, Ca); f) Granulated Carbonic Sorbent (deeppyrolysis of synthetic resin); In some embodiments, the microfluidicdialysis regenerating unit 118 a-c may further comprise a slot forreceiving a dialysate vial 136 containing fresh, unused dialysate. Inone exemplary embodiment, the microfluidic regenerating unit 118 a-c, asillustrated in FIG. 13, comprises multiple layers that are used tofilter the contaminated dialysate 122. The layers are as follows: anactivated charcoal substrate 124 a, a low porosity membrane 126 a, aurease substrate 124 b, a zirconium phosphate substrate 124 c, a highporosity membrane 126 b, and a zirconium oxide substrate 124 d.

In one embodiment, illustrated in FIG. 14, a plurality of microfluidicdialysis regenerating units 118 a-c are configured to position inside aregenerating unit housing 128. Similar to the microfluidic units/modules102 a-d, the number and size of microfluidic dialysis regeneratingmodules/units 118 a-c is adaptable to specific dialysis requirements.The modular configuration of the microfluidic unit 102 a is alsoemulated, whereby five microfluidic dialysis regenerating units 118 a-cmay be used to make up one microfluidic dialysis regenerating construct;five microfluidic dialysis regenerating constructs may be used to makeup one microfluidic dialysis regenerating module, and multiplemicrofluidic dialysis regenerating modules may be operatively fitted inthe microfluidic regenerating housing 128.

Looking now at the block diagram of FIG. 15, the dialysis is initiatedwhen blood 134 is pumped from the body 132 and circulated through thesystem 100 The micro-pumps 130 a-c force the blood 134 from the body 132to the microfluidic housing 114, which comprises a plurality ofmicrofluidic modules/units 102 a-d. The microfluidic units 102 a-doperate as discussed above. The contaminated dialysate 122 from thedialysis process in the microfluidic housing 114 is then redirected toan external filtering process consisting of a forward dialysis 138, areverse osmosis system 140, and a waste reservoir 142 for filtering outthe water, toxins, and small electrolytes.

The reverse osmosis system 140 discussed for the external filteringprocess may utilize a reverse osmosis micro-pump to push water through asemipermeable membrane or filter which removes almost all of thecontaminants in the contaminated dialysate 122, including bacteria andviruses. Other parts of the portable reverse osmosis system 140 mayinclude a carbon filter which absorbs the chemicals added by the waterdepartment and a sediment filter which traps large pieces of debris. Itis significant to note that if the water is very hard, a softener mayalso be installed which removes calcium and magnesium because thesesubstances could damage the reverse osmosis system 140. In otherembodiments, the reverse osmosis system 140 may produce two types ofwater: product water and reject water. The product water is theultrapure water which enters the microfluidic housing 114 and is used tomix the dialysate for dialysis treatment. The reject water contains thebacteria that was cleaned out of the water and is sent to the waterreservoir and down the drain for discarding.

From this external filtering process, the partially filtered dialysateflows to the microfluidic regenerating housing 128, which contains aplurality of microfluidic regenerating units/modules 118 a-c for finalfiltering. A dialysate vial 136 may also be used to replenish theregenerated dialysate 120. The regenerated dialysate 120 then flows backto the microfluidic housing 114 for further dialysis processing.

In one optional embodiment, the system 100 further comprises one or morewarming devices (not shown) that are configured to activate charcoal andother components of the device as desired. One or more cooling devices(not shown) may also be used to cool the heated components and also toreturn the blood 134 to normal temperatures. For example, blood 134 maybe warmed through the warming device and cooled through the coolingdevice, such that the dialysate 116 returns to the vile in themicrofluidic dialysis regenerating unit 118 a-c in a concentrated form.The warming device may be configured to warm the blood 134 to about 42°Celsius, after passing through the microfluidic unit. The cooling devicemay be configured to cool the plasma portion down to 35° Celsius, afterpassing through the microfluidic housing 128.

As discussed above, the system 100 is configured in a device. The deviceincorporates a machine that controls the therapy parameters and includesstate of the art microfluidic-based dialyzer for performing thediffusive and convective dialysis as well as other filters/semipermeablemembranes for the regeneration of the dialysate 116 thus enabling thesystem 100 to perform a complete dialysis treatment using small quantityof potable tap water. Parts of this device are a single-use disposablecassette. The electronic circuits in the device may include withoutlimitation, a sensor control board, micro-pumps drivers, a mainprocessor board, a type BF power supply, a power management circuit, ashort term battery back-up, and a Wi-Fi dialysis filter component.

Further, the system 100 may include a user interface for monitoring I/Oand net volume of blood 134 circulation. In additional embodiments,volume is monitored and adjusted, and a filter may be introduced forsafety to trap any carbon/particulate matter and remove thecarbon/particulate matter from the cellular portion before reenteringthe patient. The device may further include a bubble trap, a charcoaltrap, and various filters for safely trapping any carbon/particulatematter and removing it from the cellular portion of the blood 134 beforereentering the body 132 of the patient.

The Plasma Portion (P.P.-cell free portion) is directed to a chip modulewith a special design with a multilayer microfluidic chipset modulecomprising at least 5 layers. The middle layer is sandwiched between twomirror image layers. The P.P. is located in the central layer which issandwiched between two identical layers containing dialysate+Albumin.These three layers are sandwiched between two identical layerscontaining dialysate+charcoal. The four membranes separating all fivelayers have characteristics of a High Molecular Weight Cut-Off (HMWCO)dialysis membrane in order to achieve albumin dialysis.

A multilayered microfluidic chipset unit/module for more efficientalbumin dialysis. (The MCAL Technology microfluidic chipset ADunit/module).

A multilayered microfluidic chipset module-AD Module-is designed forperforming much more efficient albumin dialysis and removal of theprotein/albumin-bound toxins. This chipset design is unique since thealbumin regeneration is built on the chip.

A 5-layered inert and biocompatible polymer used as microfluidicsubstrate such as PDMS based microfluidic chipset module. A single layerof microfluidic for blood compartment (blood layer) sandwiched betweentwo two-layered charcoal and albumin dialysate layers placed in mirrorimage as described below:

1. 1^(st) layer . . . Dialysate with charcoal Flow →→→ 2. 2^(nd) layer .. . Dialysate with albumin Flow  

3. 3^(rd) layer . . . Plasma Portion (P.P.) Flow →→→ from plasmapheresis4. 4^(th) layer. . . Dialysate with albumin Flow  

5. 5^(th) layer . . . Dialysate with charcoal Flow →→→

Between each of the following layers, the 1^(st) & 2^(nd), 2^(nd) &3^(rd), 3^(rd) & 4^(th) and 4^(th) & 5^(th) layers, a high flux membrane(or other membranes) will be placed to separate each layer compartmentand provide the needed membrane surface for dialysis to occur It issignificant to note that all fluids flow in a countercurrent or angledcountercurrent direction in respect to their adjacent layers

1. 1^(st) layer . . . Dialysate with charcoal Depth of channels 20-200um2. 2^(nd) layer . . . Dialysate with albumin Depth of channels 20-200um3. 3^(rd) layer . . . Plasma Portion (P.P.) Depth of channels 20-100umfrom plasmapheresis 4. 4^(th) (same as 2^(nd) layer) . . . DialysateDepth of channels 20-200um with albumin 5. 5^(th) (same as 1^(st) layer). . . Dialysate Depth of channels 20-200um with charcoal

Note: the flow of each layer will be manipulated and optimal directionof flow can be optimized and studied. The concurrent, countercurrent aswell as tangential cross flows will be investigated, for best andoptimal efficiency. The membranes used can vary but high flux or evenmembranes with higher MWCO characteristics may be utilized. In additionthe rate of flow for each layer will be studied and optimized. The finalchipset will have the ability to provide sampling and up to datemonitoring of certain chemical and physiological values using biosensorsembedded into the chip design.

Turning now to FIG. 16, the system 100 may be effective for fabricatinga bio-artificial liver 144 through substantially the same microfluidicprinciples discussed above. The bio-artificial liver 144 comprisessubstantially the same microfluidic units 102 a-d, but in a more layeredconfiguration that is consistent with the human organs.

In conclusion, the combined microfluidic based kidney and Liver dialysisdevice for MODS/sepsis system for removing middle molecular weighturemic toxins and small solutes, protein-bound uremic and hepatictoxins, and water from the blood through the use of microfluidictechnology, and various embodiments thereof is provided.

Since many modifications, variations, and changes in detail can be madeto the described preferred embodiments of the invention, it is intendedthat all matters in the foregoing description and shown in theaccompanying drawings be interpreted as illustrative and not in alimiting sense. Thus, the scope of the invention should be determined bythe appended claims and their legal equivalence.

Combined Microfluidic Based Kidney and Liver Dialysis Device forMODS/Sepsis

The combined microfluidic-based Kidney and Liver Dialysis Device iscomposed of various biomimetically designed modular andmicrofluidic-based microfluidic chipset units based on The MCALTechnology. These combinations and permutations basic units that areassembled by connecting them in parallel or in series fashion. The finalmicrofluidic device and its microfluidic chipset units may be placed inseries on one larger single microfluidic chip. It should be noted thatthese microfluidic chipset units/modules/(The MCAL Technology basicunits) may be assembled together in different permutation to allowunique development of other organ supports/replacement devices,bio-artificial organs support systems as well as portable dialysisdevices.

The microfluidic Kidney/Liver Replacement dialysis device will haveseveral permutations of 9 major modules/MCAL Technology microfluidicchipset units/modules depending on the final design of the project, eachMCAL Technology module with a different and unique function. Eachdifferent unit/module is designed to emulate certain function of kidneyand/or liver functions. Some of these MCAL Technology units/modules areoptional.

It should be noted that all the dialysis devices, bioreactor organs,bio-artificial organ devices will include all the necessary and standardthe micro-pumps, sensors, filters, and various alarms used inconstructing these machines and also CRRT and HD/HP. These importantcomponents are not shown for the sake of simplicity.

These 9 microfluidic chipset units (modules) of the microfluidicKidney/Liver Replacement Device are as follows:

1. PS module (Plasma Separation/Plasmapheresis) 2. HD module(Hemodialysis) 3. HP module (Hemoperfusion) 4. HDF and/or DF module(Hemodiafiltration) and/or (Diafiltration) 5. AD module (AlbuminDialysis) 6. ADR module (Optional-Regeneration of Albumin Dialysate) 7.DR module (Optional-Dialysate Regeneration) 8. LD module (Optional-LipidDialysis) 9. BR Module (Optional-Bioreactor Organ)

The 9th MFC may be used to construct the Bio-Artificial by adding it inseries to the microfluidic Kidney/Liver Replacement

Here are a few simple devices schematically presented to showdevelopment of three different yet similar Dialysis/support devices.Microfluidic Kidney/Liver Replacement DeviceAll the above have the option to be used with Lipid Dialysis by addingthe LD microfluidic chipset unit of the MCAL Technology.

Bio-Artificial Microfluidic Kidney/Liver Replacement Device

Any one of the above microfluidic Kidney/Liver Replacement designs withaddition of a Bio-Artificial bio-reactor. The BR module is added beforethe blood is returned to the patient (BTP)All the above have the option to be used with Lipid Dialysis by addingthe LD MCAL

Technology Unit/Module

Portable microfluidic Kidney/Liver Replacement Device

I. The MCAL Technology Microfluidic Chipset Unit/Module—the PS Module

This MCAL Technology microfluidic chipset (unit/module) which isplasmapheresis membrane that is sandwiched in between two inert andbiocompatible polymers used as microfluidic substrate such PDMS (mirrorimage of each other) with specific aspect ratio to increase thediffusion.

The anticoagulated blood from patient is pumped, and then isanticoagulated (not performed here) before entering the first module ofthe device-the PS module. The PS module which emulates the function of aglomerulus in human nephron is where Plasmapheresis Membrane is utilizedand will allow the plasma proteins to be filtered. Therefore, the PSmodule will filter all non-cellular components of the whole blood andgenerate two portions from the whole blood from patient entering it.

Cell portion is the portion containing mostly the cellular elements ofthe blood (WBC, RBC, Platelets) and some plasma. The composition of theplasma is not changed, only the plasma is separated from the wholeblood. The hematocrit will be increased from 30-40% to about 50-70%coagulated. This portion is either returned to the patient or isdelivered to a bioreactor if available). Meanwhile, the Plasma Portionis the portion containing non-cellular components of the whole blood(all proteins, electrolytes, and albumin). This is also anticoagulatedwill have hematocrit of 0% ready to be entered the next module. Beforeit goes to the next module it will be diluted 1:1 to 4:1 by adding 1-4parts replacement fluid (various FR with different compositions such asnormal saline or bicarbonate based fluid and etc.)

II the MCAL Technology Microfluidic Chipset Unit-the HD Module

This microfluidic chip at this module has a simple design of ahemodialysis membrane which is sandwiched in between two PDMS (mirrorimage of each other) with specific aspect ratio to increase thediffusion, convection via internal filtration.

The diluted PP portion enters the next module which is the HD module. Inthis module the PP will be dialyzed very well and composition of theplasma will change drastically. Since there is a diffusive andconvective process involved, there is another input into the MFC-thedialysate.

The diluted and anticoagulated P.P. from previous module-PS module whichhas Hct of 0% will enter the MFC-the HD module which emulates thefiltration function of the glomerulus in the human nephron. The PP willundergo an intensive diffusive dialysis against the fresh dialysate andalso a convective dialysis via ultrafiltration. Of course a freshdialysate is used during this process which will be regenerated throughthe R module if available or discarded.

The outflow of the HD module which is a well dialyzed and moreconcentrated PP is directed to the next module of the dialysis device.

III the MCAL Technology Microfluidic Chipset Unit—HP Module

This microfluidic chip at this module has a simple design of aspecialized PDMS micro-reservoirs where microfluidic channels lead intoand out of, directing the flow of the PP over these reservoirs thatcontain a combination of resins and charcoal to perform thehemoperfusion more efficiently.

A well dialyzed and more concentrated PP is directed to this module-theHP module. The HP module emulates the function of the tubular portion ofhuman nephron. The PP now enters the HP module where hemoperfusion isperformed using charcoal and resin. The PP will be hemoperfused againstthe resin and charcoal to remove the tightly bound protein-bound toxinsfrom the PP. The PP is further cleared from protein-bound toxins duringthis module. The PP then is directed to the next module-the albumindialysis module-AD module. Note; the AD module may be replaced by ADRmodule which has the capability of regenerating the albumin for use byrecirculation.

The MCAL Technology Microfluidic Chipset Unit/Module-HDF Module

This microfluidic chip at this module has a simple design of ahemodiafiltration membrane which is sandwiched in between two PDMSMFCs;-one PDMS with specialized cannels with specific aspect ratio toincrease the diffusion, convection and the other PDMS with a special(see design of the MCAL Technology).

The HDF module of the MCAL Technology is used to regenerate the spentdialysate using a reservoir of charcoal and/or various resins andsubstances. The spent dialysate containing albumin(Dialysate+Albumin—Dial/Alb) enters the MCAL Technology-HDF againstanother input of the fresh dialysate containing charcoal and resin(Dial/Ch & R) solution from its reservoir separated by thehemodiafiltration membrane. The regenerated dialysate with albumin(Dial/Alb) is returned to MCAL Technology module A and the spentdialysate containing charcoal and resin(Dialysate+Charcoal+/−Resins-Dial/Ch & R) is returned to the reservoircontaining the fresh Dial/Ch & R.

The MCAL Technology microfluidic Chipset unit/module—ADR (AlbuminDialysis Regeneration) module.

A multilayered PDMS based Microfluidic Chipset unit/module for moreefficient albumin dialysis.

A multilayered PDMS microfluidic chipset is designed for performing muchmore efficient albumin dialysis and removal of the protein/albumin-boundtoxins This chip design is unique since the albumin regeneration isbuilt on the chip.

A 5-layered PDMS based microfluidic chipset. A single layer of PDMS forblood compartment (blood layer) sandwiched between two two-layeredcharcoal and albumin dialysate layers placed in mirror image asdescribed below:

1. 1^(st) layer . . . Dialysate with charcoal Flow →→→ 2. 2^(nd) layer .. . Dialysate with albumin Flow  

3. 3^(rd) layer . . . Plasma Portion (P.P.) Flow →→→ from plasmapheresis4. 4^(th) layer . . . Dialysate with albumin Flow  

5. 5^(th) layer . . . Dialysate with charcoal Flow →→→

Between each of the following layers, the 1^(st) & 2^(nd), 2^(nd) &3^(rd), 3^(rd) & 4^(th) and 4^(th) & 5^(th) layers, a high flux membrane(or other semipermeable membranes) will be placed to separate each layercompartment and provide the surface for dialysis to occur.

Note: All fluids flow in a countercurrent direction respect to theiradjacent layers.

1. 1^(st) layer . . . Dialysate with charcoal Depth of channels 20-200um2. 2^(nd) layer . . . Dialysate with albumin Depth of channels 20-200um3. 3^(rd) layer . . . Plasma Portion Depth of channels 20-100um (P.P.)from plasmapheresis 4. 4^(th) (same as 2^(nd) layer) . . . DialysateDepth of channels 20-200um with albumin 5. 5^(th) (same as 1^(st) layer). . . Dialysate Depth of channels 20-200um with charcoal

The concurrent, countercurrent as well as tangential cross flows may beused for best and optimal efficiency.

The membranes used can vary but high flux or even membranes with higherMWCO characteristics may be utilized. The diluted and well dialyzed PPenters this module-the AD module which emulates the function of thetubule portion of the human nephron. The diluted PP enters the AD modulewhere albumin dialysis is performed using High-Molecular-Weight Cut-off(HMWCO) value membrane/High Performance Membrane which allows the PP tobe dialyzed against albumin or a combination of albumin pluscharcoal/resin. The first output of the MCAL Technology-the PPportion-will be directed back to the patient/subject while the secondoutput of this module-the spent albumin dialysate-will be directed tothe module D for regeneration.

The MCAL Technology Albumin Dialysis unit/module-The AD module.

Multilayered microfluidic-based (using inert and biocompatible polymerssuch as PDMS or other substrates) Microfluidic Chipset unit/module foralbumin dialysis.

A multilayered microfluidic chipset is designed for performing much moreefficient albumin dialysis and removal of the protein/albumin-boundtoxins. A multilayered microfluidic chipset unit/module with a singlelayer of microfluidic micro-channels for blood/plasma compartment (bloodlayer) sandwiched between two albumin dialysate layers placed in mirrorimage as described below:

1. 1^(st) layer . . . Dialysate Flow  

with albumin 2. 2^(nd) layer . . . Plasma Portion Flow →→→ fromplasmapheresis 3. 3^(rd) layer . . . Dialysate Flow  

with albumin

The MCAL Technology microfluidic Chipset unit/module—The DR module(optional)

This microfluidic chip at this module has a simple design of a reverseosmosis membrane which is sandwiched in between two layers ofmicrofluidic micro-channels microfluidic chips; the PDMS withspecialized cannels with specific aspect ratio to increase the diffusionof pure water and the output is the concentrated dialysate with all theelectrolytes and toxins The water that is passes to the other PDMS willbe directed as pure water for dialysate regeneration as needed. The DRmodule (MCAL Technology-DR) is used to regenerate the spent dialysate.It has been designed to bypass the obstacles of an RO system. Its waterpurification system consists of the following parts:

-   -   a sediment filter which removes large particles from the water    -   an ultraviolet light tray which kills bacteria and breaks down        chemicals in the water (not required)    -   a carbon filter which adsorbs chemicals in the water    -   a dual bed DI resin which removes dissolved electrolytes    -   a mixed bed DI resin as a backup and safety net to the previous        DI Resin    -   an ultrafilter to remove bacteria (not required)    -   a 0.2 micron filter which removes any bacteria that may have        been introduced into the system so it will not reach the patient    -   Cold Plasma generation for sterilization (optional-use of either        Direct or indirect cold plasma generation using air or O₂)

Components of the Dialysis Regenerating Unit

1. Activated Charcoal (1 gram=500 m2 surface area

2. Urease (NH₂CO+H₂O→CO₂+2NH₃)

3. Zirconium Phosphate

4. Zirconium Oxide plus Zirconium carbonate

5. Composite Dry Chemical (to Mix in with K, Mg, Ca)

Kremezin Adsorbent to be Used Here Also Granulated Carbonic Sorbent(Deep Pyrolysis of Synthetic Resin)

A reverse osmosis membrane and combination of Zirconium and activatedcharcoal. The spent dialysate containing all electrolytes and toxinsenters the microfluidic chipset module-DR against the above componentsand the output can be used to generate fresh dialysate for the requiredmodules. This DR module is mostly to be used in a portable version ofthe combined kidney and Liver Replacement device dialysis to reduce theamount of dialysate needed and thereby allowing portability andminiaturization of the dialysis device. (optional)

MCAL Technology module LD (Lipid Dialysis-Optional).

A multilayered inert and biocompatible polymer used as microfluidicsubstrate such PDMS based Microfluidic Chipset for albumin dialysis.

A multilayered inert and biocompatible polymer used as microfluidicsubstrate such PDMS microfluidic chipset is designed for performing muchmore efficient albumin dialysis and removal of the protein/albumin-boundtoxins. A 3 or multi-layered inert and biocompatible polymer used asmicrofluidic substrate such PDMS based microfluidic chipset. A singlelayer of PDMS for blood compartment (blood layer) sandwiched between twoalbumin dialysate layers placed in mirror image as described below:

1. 1^(st) layer . . . Dialysate with albumin Flow  

2. 2^(nd) layer . . . Plasma Portion from Flow →→→ plasmapheresis 3.3^(rd) layer . . . Dialysate with albumin Flow  

This module is optional.

II. MCAL Technology Module BR (Bioreactor)

This microfluidic chip module has a complex design. The MCAL Technologybioreactor will be constructed using at least three (3) layers of inertand biocompatible polymer used as microfluidic substrate such as PDMSwhich are sandwiched and are separated by two membranes with highpermeability to oxygen and nutrients (amino acids, glucose, and lipidsetc.). The central layers (the cell chamber) have the largest dimensionin order to hold a large number of desired viable cells. This chamber isfilled with pre-specified numbers of encapsulated cells (kidney and/orliver cells in hydrogel) which are placed inside the cell chamber. Thechamber is kept open by pillars that are placed strategically across thearea to avoid collapsing of the two membranes one each side separatingit from the other two layers. The other two PDMS layers that sandwichthis cell chamber are wide enough for easy flow of the diluted C.P thatis oxygenated! These two layers will provide the central chamber whichcontains the live cells, with their appropriate oxygen and nutrients,and removes the co2 generated Meanwhile the central layer is bathed bythe P.P. after (maybe before) it has gone through intensive dialysis forremoval of the toxins to avoid cell damage!

It should be noted that the central chamber can be filled with varioustissues, cells, cell supporting elements, stem cells, encapsulated cellsand/or combination of two or more of these tissue components. Thismicrofluidic bioreactor organ unit will be placed in series with theartificial liver and/or artificial kidney) to form theBio-Artificial-microfluidic based Kidney and Liver Replacement Device-abio-artificial organ unit.

By combining microfluidics and soft-lithographic molding of gelscontaining mammalian cells, a device for three-dimensional (3D) cultureof mammalian cells in microchannels will be manufactured. Nativecomponents of the extracellular matrix, including collagen or Matrigel,make up the matrix of each molded piece (module) of cell-containing gel.Each module will have at least one dimension below −300 um; in modulesof these sizes, the flux of oxygen, nutrients, and metabolic productsinto and out of the modules will be sufficient to allow cells in themodules to proliferate to densities comparable to those of native tissue(108-109 cells/cm3). These modules will be packed loosely intomicrofluidic channels and chambers yielding structures permeated with anetwork of pores through which cell culture medium could flow to feedthe cells as well as encapsulated cells.

The two outer mirror image microfluidic layers that sandwich the centralcell chamber (holding living cells) are wide enough for easy flow of thediluted cellular portion (C.P.) that is oxygenated! The design of themicrochannels is to avoid clotting and cell damage to the cellularcomponents of the blood such as RBCs, WBCs and platelets. These twolayers will provide the central chamber which contains the live tissuecells and its components, with their appropriate oxygen and somenutrients, while removing the CO2 generated.

Meanwhile to keep the bioreactor cells healthy and functioning, thecentral layer containing the live cells will be bathed by the plasmaportion (P.P.) which has plenty of macro- and micro-nutrient.Additionally, PP has many toxins that may be still present(protein-bound) as well as lacking proteins that are synthesizedregularly by the organ (e.g. kidney, liver) hence providing thesynthesis function of the organ that is missing. The PP portion mayenter the MCAL Technology microfluidic chipset BR module-the bioreactormodule/unit-after intensive dialysis for removal of the toxins to avoidcell damage or before it has gone through other modules. Then, these twooutputs from the module BR are mixed and returned to the subject.

Mobile, modular and scalable microfluidic-based kidney and/or liverdialysis Device.

The present invention is a portable, compact, lightweight,self-contained hemodialysis machine for in-home or on the gohemodialysis device delivery machine, utilizing various biomimeticallydesigned MCAL Technology microfluidic chipset units with ability forattaining higher diffusive and convective forces beyond the currentlyachievable uremic toxin clearances using the hollow fiber technology.FIG. 10 illustrates a comparison Table 162 that differentiates theHollow Fiber Technology and MFC technology.

In addition, this microfluidic-based dialysis device requires lowerblood volume and lower blood flow rates. Furthermore, the device ismodular and scalable which can be adjusted to the patient's body surfacearea (BSA) & body weight as well to ensure individualization of therapyfor all types of patients from pediatrics to adult which requiredifferent dialysis need. Being an adjustable dialysis unit, it is easyto achieve the targeted dialysis treatment. One size fits all will notbe acceptable in hemodialysis any longer.

This portable and/or wearable hemodialysis device is based on the MCALTechnology. The device is a stand-alone hemodialysis device with uniquedesign that replaces the currently available standard hollow fibertechnology based dialysis which is very inefficient. Themicrofluidic-based dialyzers and filters will improve the efficiency ofthe dialysis several magnitudes. In addition, utilizing thesebiomimetically designed microfluidic-based chipset units willdrastically increase middle molecular uremic toxins and protein-boundtoxin removal via slow and highly efficient microfluidic-based dialyzertechnology which ultimately will improve the morbidity and mortality ofthese patients and overall and also decrease healthcare cost and burdenof ESRD treatment.

The device is a light-weight dialysis unit with miniaturized componentswhich can run continuously or intermittently operating from 6-24/dayseven days a week This allows gentle ultrafiltration to avoid severepost-dialysis fatigue and fluid shifts seen by regular HD. Acomputerized WIFI/remote feedback/interface/control of the device willallow minute to minute monitoring of important physiological as well asmechanical parameters.

Furthermore, this device will have the capacity regenerate dialysatefluid to minimize the amount of dialysate used daily to as little as˜300 ml to 1500 ml/day Utilizing the microfluidic-based MCAL Technologyunits it can generate ultrapure dialysate which ultimately reduceinflammatory cytokines and ultimately mortality of patients.

Microfluidic Chipset Units:

Utilizing the various biomimetically designed microfluidic-based MCALTechnology microfluidic chipset units in the following ways.

MCAL Technology Based Microfluidic Chipset Unit Dialysate RegenerationModule

This PDMS microfluidic chip has Activated Charcoal/Polystyrene and otherregenerating compounds placed in layers separated with semipermeablemembrane with pores only allowing water and small electrolyte passage.Therefore the spent dialysate will pass through all the layers of theMCAL technology based microfluidic chipset Dialysate RegeneratingUnit/module.

Design and Components of Dialysate Regeneration Module

This component is designed to refresh and regenerate the spentdialysate, by removing the toxins as well as correcting the electrolyteand its PH. In order to achieve portability, reduction in size thedialysate fluid has to be much smaller than the amount used in regularstandard hemodialysis

A regular cube vs. cylinder filled with the appropriate sorbents andcharcoals

There are Two Designs for this Component:

1. Regular Dialysate Regeneration Unit (rDRU)2. Microfluidic Dialysate Regeneration Unit (mDRU)

Regular Dialysate Regeneration Unit DRU (rDRU)

A container (various shapes including cube, cylinder etc.) packed withsorbet material with a special connection for attachment of newdialysate ampoule to the mobile, modular and scalable microfluidic-basedkidney and/or liver dialysis Device

Via the DRU

The regular (non-microfluidic) DR module—is a rectangular cube withdimensions equaling 300-1000 ml (300-1000 cm3) [i.e. 10 cm×10 cm×7 cmwhich is packed with 3-4 layers of carbon fibers, zirconium carbonate,Zirconium phosphate, urease, etc.

The DRU has a special slot for inserting a vial of fresh Dialysate. ThisDialysate vial can be changed as needed.

MCAL Technology Based Microfluidic Dialysis Regenerating Module

The microfluidic chipset DR module has a Dialysate Regenerating Unitwhich has been designed to bypass the obstacles of an RO system. Itswater purification system, consists of the following parts

a sediment filter which removes large particles from the wateran ultraviolet light tray which kills bacteria and breaks down chemicalsin the water (not required)a carbon filter which adsorbs chemicals in the watera dual bed DI resin which removes dissolved electrolytesa mixed bed DI resin as a backup and safety net to the previous DI Resinan ultrafilter to remove bacteria (not required)a 0.2 micron filter which removes any bacteria that may have beenintroduced into the system so it will not reach the patientCold Plasma generation for sterilization (optional)

The microfluidic chipset DR module has the advantage of using less waterthan an RO, only about 300-1500 cc/per treatment

Components of the Dialysis Regenerating Unit

1. Activated Charcoal (1 gram=500 m2 surface area

2. Urease (NH2CO+H20→CO2+2NH3 3. Zirconium Phosphate

4. Zirconium Oxide plus Zirconium carbonate5. Composite Dry Chemical (to Mix in with K, Mg, Ca)

Granulated Carbonic Sorbent (Deep Pyrolysis of Synthetic Resin)

The Reverse Osmosis (RO) System

The reverse osmosis (RO) system uses a micro-pump to push water througha semipermeable membrane or filter which removes almost all of thecontaminants including bacteria and viruses. Other parts of a portableRO machine include a carbon filter which absorbs the chemicals added bythe water department and a sediment filter which traps large pieces ofdebris. If the water is very hard, a softener may also be installedwhich removes calcium and magnesium because these substances coulddamage the RO system.

The RO machine produces two types of water: product water and rejectwater. The product water is the ultrapure water which enters thehemodialysis machine and is used to mix the dialysate for your dialysistreatment. The reject water contains the bacteria that was cleaned outof the water and is sent down the drain and discarded.

Therefore, the mobile, modular and scalable microfluidic-based kidneyand/or liver dialysis device can accommodate to different catabolicneeds in addition to patients weight and surface area for optimaldialysis.

Micro-Pumps

At least 7 micro-pumps are needed for the mobile, modular and scalablemicrofluidic-based kidney and/or liver dialysis Device.

1. Blood Pump (2) 2. Heparin Pump (1) 3. U/F Pump (1) 4. Dialysate Pump(2)

May use two different micro-pumps 1) Pneumatic and 2) Electric

1. Pneumatic Micro-Pump (Balloon Hand/Palm Pump)—OPTIONAL

The pneumatic pump is a manual balloon hand pump that can be used togenerate and store a pressurized atmospheric air in a special reservoirfor storage of compressed air called CAR (CAR-Compressed Air Reservoir).This pressurized air will be used to run the pneumatic pumps to loweruse of battery power. In addition, these can be used manually toregenerate power.

The CAR unit has a balloon hand pump which can be used to manually fillthe Compressed Air Reservoir as needed. The CAR unit will dispense aspecified amount of air to run the pneumatic pumps at a certain rate.These pneumatic micro-pumps also have back-up battery powered electricalmicro-pump.

2. Electric Micro-Pump

These micro-pumps run on the rechargeable battery of the unit.

Cooling and Heating of the Dialysate

Use of these two modalities (cooling and heating) is to increase theActivated Charcoal absorption and desorption. This may add to the weightof the unit Patient's body temperature may be used.

Ultrapure Dialysate

Ultrapure fluid has been associated with better health outcomes as wellas less inflammation. Definition of Ultrapure Dialysate: Bacteria <0.1CFU/ml; Endotoxins <0.03 IU/ml Need smaller amount for the MKD Use theDiasafe membrane by Fresenius to generate an ultrapure dialysate whenconstructing the chipset. Backfiltration and back diffusion areextremely important clinically especially for sicker patients.

Major disadvantages of high flux dialyzer membranes are theBackfiltration of Endotoxin fragments and other inflammatory provokingsubstances.

Forward Osmosis for Dialysate Regeneration (Optional)

Water is drawn across a semipermeable but solute impermeable-from thefeed solution (Spent Dialysate) to Draw solution (high concentration ofNa plus bicarbonate in this case).

The spent dialysate (after several runs) will be added to a bicarbonatecontainer separated from the spent dialysate by a Cellulose Acetatemembrane to achieve a Forward Osmosis.

1. The Feed fluid=Spent Dialysate2. The Draw fluid=High concentration of Bicarbonate Sodium3. The membrane=Cellulose Acetate4. Input from the output of the Dialysate Microfluidic Chipset5. Output to the dialysate regeneration unit

The Organ Support and Replacement

Use of the MCAL Technology in Designing Bioreactor for Different Typesof Artificial Organ Modules

The Bioreactor Design and Function—The microfluidic platform will befabricated from inert and biocompatible substrates used in manufacturingmicrofluidics For example, PDMS and the chitosan fibers wound on a framewill be embedded in a PDMS platform, and HepG2 cells will be seeded andcultured forming clusters around the microfibers.

By combining microfluidics and soft-lithographic molding of gelscontaining mammalian cells, a device for three-dimensional (3D) cultureof mammalian cells in microchannels is developed. Native components ofthe extracellular matrix, including collagen or Matrigel, make up thematrix of each molded piece (module) of cell-containing gel. Each modulehad at least one dimension below ˜300 um; in modules of these sizes, theflux of oxygen, nutrients, and metabolic products into and out of themodules was sufficient to allow cells in the modules to proliferate todensities comparable to those of native tissue (10⁸-10⁹ cells/cm³).Packing modules loosely into microfluidic channels and chambers yieldedstructures permeated with a network of pores through which cell culturemedium could flow to feed the encapsulated cells. The order in thepacked assemblies increased as the width of the microchannels approachedthe width of the modules. Multiple cell types could be spatiallyorganized in the small microfluidic channels. For many types of cells,behavior in two-dimensional (2D) culture differs from that inthree-dimensional (3D) culture. Among biologists, 2D culture on treatedplastic surfaces is currently the most popular method for cell culture.In 3D, no analogous standard method—one that is similarly convenient,flexible, and reproducible—exists.

Single Organ Unit of Liver, Kidney, Pancreas and Etc. The lobule/ororgan unit will be constructed as follows:

Three or more layers of the microfluidic microchannels are separated bytwo or more semipermeable membranes with good permeability to oxygen andnutrients (amino acids, glucose, and lipids etc.). The central layers(the cell chamber) have the largest dimension in order to hold a largenumber of desired viable cells. This chamber is filled withpre-specified numbers of encapsulated cells (kidney or liver cells inhydrogel) which are placed inside the cell chamber. The chamber is keptopen by pillars that are placed strategically across the area to avoidcollapsing of the two membranes one each side separating it from theother two layers. The other two PDMS layers that sandwich this cellchamber is wide enough for easy flow of the diluted C.P. that isoxygenated These two layers will provide the central chamber whichcontains the live cells, with their appropriate oxygen and nutrients,and removes the co2 generated. Meanwhile the central layer is bathed bythe P.P. after (maybe before) it has gone through intensive dialysis forremoval of the toxins to avoid cell damage.

It should be noted that the central chamber can be filled with manydifferent tissues, cells stem cells and other components as well asliver cells, kidney cells, combination of the two in mixture oralternating a specified volume of each encapsulated cells desired-liverand kidney. This organ unit will be placed in series with the combinedmicrofluidic-based kidney and Liver dialysis device for MODS (artificialliver) or Mobile, and modular microfluidic dialysis device delivery(artificial kidney) to form the biomimetically designedmicrofluidic-based Bio-artificial kidney or Liver dialysis device forMODS.

Biomimetically Designed MCAL Technology Based Microfluidic ChipsetBioreactor Unit Module/(Liver Tissue/Cells are Used as an Example Here)

The Bioreactor organ (here Liver is used as an example) is abiomimetically designed microfluidic-based bioartificial liverreplacement for an In Vivo and/or Ex Vivo use.These uniquely designed microfluidic-based bioreactors are based on theMCAL Technology which are intended to be

-   -   a. Modular    -   b. Scalable    -   c. Immunoisolated (no need for immunosuppression)    -   d. Well-oxygenated    -   e. Well-nourished        For Ex Vivo model it would have several additional unique        characteristics such as:    -   a. Adjustable    -   b. Nanosensors for continuous monitoring    -   c. Replenishable        The microchannels and the microreservoirs having micron size        dimension ranging from 10-2000 micron and different heights to        maximize diffusion and convection of the desirable substances        such as blood, blood components, plasma, plasma components,        dialysate, fluids with different properties and contents, oxygen        and other gases, micro- and macro-nutrients, hormones, growth        factor, etc. Additionally the surface of these        chambers/reservoirs/channels will be modified and covered with        appropriate and necessary ECM/Collagen material or other tissue        components to make the desired tissue/organ/cell/MSCs/Stem cells        grow and stay viable.        The microfluidic bioreactor organ is a macro-chamber that is        rectangular shaped, consisting of several major components that        are integrated. It consists of two modules:    -   1. Plasma Separator    -   2. The Bioreactor        This device has a special design with at least two main        permutations. This permutation is based on the simple option of        where to direct the plasma portion (P.P.) output from the MCAL        Technology based plasma separator module-PS chipset        unit/module/module. There are basically two main designs:    -   1. Indirect Exposure of the Cells with Plasma Portion (P.P.)    -   2. Direct Exposure of the Cells with Plasma Portion (P.P.)        Note: there could be other permutation of these two designs        using microfluidic chips

Overview of the Scheme of the Biomimetically Designed Bioreactor Organ:

The artificial bioreactor organ (here liver is used as an example)consisting of several modules which are placed serially eithercontinuously on the same chipset module, or disjointed on differentchipsets that are connected serially to emulate a human organ/tissuesuch as liver lobule. A large collection of these “artificial organunits/modules make up an artificial bioreactor organ. Due to the factthese modules are simple basic units and can be added, remover, orreplaced the ultimate design would have the capability of replacing anyone of these chips modules if they fail to work properly, withoutdisrupting the function of the other organ units!The modules are as follows:

MCAL Technology Based PS Module (Plasma Separation Chipset Module)

This microfluidic module will use a plasmapheresis membrane over amicrofluidic channels to perform a plasmapheresis or cytapheresis.Thereby, the input of the whole blood through this module will have twooutputs 1) the cell portion (C.P.), which mainly contains the cellularcomponents of the whole blood in small amount of plasma 2) the plasmaportion (P.P.), which is devoid of any cellular elements. The C.P.output is then immediately directed to the bioreactor construct is aseparate line, while the P.P. is directed to the bioreactor after goingthrough the module 2.

MCAL Technology Based BR Module (Bioreactor Chipset Module)

This microfluidic Bioreactor will use a multilayer inert andbiocompatible polymers for microfluidic substrate such as PDMS constructto achieve:1. Oxygenate and provide nutrients as well as removal of the CO2 usingthe C.P. which has a high hematocrit. The C.P. is directed to the outertwo layers of the bioreactor (see bioreactor function and design). Thenutrient and the oxygen are delivered via two permeable membrane.2. To bathe the hepatocytes in the hydrogel with the “dialyzed” P.P.from module #1 this will enter the central layer of the bioreactor.Hence the toxins removed by the bioreactor.

The Description of the Bioreactor Organ for In Vivo Use and itsComponents First Design

The Microfluidic Bioreactor is a macro-chamber that may have variousshapes such as circular, rectangular or other shapes, consisting ofseveral major components that are integrated.

MCAL Technology Based Chipset PS Module 1: The Plasma Separator Module

-   -   1. Whole blood enters the Bio-Artificial Liver Device.    -   2. The first module of this device is where plasma portion (P.P)        as well as cellular portion (C.P) components of the whole blood        is separated.    -   3. This is accomplished using a plasmapheresis membrane.    -   4. The P portion is further separated into a Rich Plasma Portion        (RPP) and Serum Portion (SP) without the plasma proteins.    -   5. The RPP will be returned to the patient.    -   6. The S portion which contains he micro and macro nutrients are        diverted to the next module.    -   7. The C portion is further separated into RBC portion and the        WBC/Platelets portion.    -   8. The WBC portion is returned to the patient.    -   9. The RBC+Platelets portion is directed to the next module.    -   10. The next module is a microfluidic multilayer PDMS construct        that has multiple copies of a two layered microfluidic channels        that are alternating while being separated by ECMO membranes.

MCAL Technology Based Chipset BR Module 2: The Bioreactor Module

There is no Direct Flow of the plasma portion over the cells/tissue/stemcells and other cellular components+ECMThis module is a repetition of an organ unit that is composed of threeor more layers of microfluidic channels/reservoirs and different typesof semipermeable membranes that are constructed as follow:

I. Layer Ax:

Microfluidic channels for the passage of RBC portion in parallel to thehepatocytes This layer as well as other similarly designed layers (Ax1,Ax2, Ax3, etc.) will receive the RBC rich portion from the previousmodule. This fluid will support the vital oxygen needed for the properfunctioning of the tissue, cells, and stem cells. The oxygen will flowthrough the ECMO membrane (Layer Me-ECMO membrane).

II. Layer Me:

The Membrane Oxygenator that is a typical Extra Corporeal MembraneOxygenatorThis layer is a membrane that separates the two microfluidic layers andallows the RBC portion in the Layer B to provide oxygen for the in theLayer A without direct intact with them.

III. Layer Bx:

These Microfluidic channels holds tissue, cells, stem cells hepatocytesor other needed tissue components (stem cells as well as ECM) inMicroreservoirs. This layer as well as other similarly designed layers(Bx1, Bx2, Bx3, etc.) will receive not come in contact with the PlasmaPortion from previous module. This fluid will diffuse through a membrane(layer Mh-HMWCO membrane) to provide the tissue, cells, stem cells, MSCwith macro and micronutrients requirements as well as the glucose.

IV. Layer Mh:

The high molecular weight cut-off membrane (HMWCO) separates the twomicrofluidic layers and provides the microencapsulated MSC/Hepatocyteswith macro and micronutrients requirements as well as the glucose. Thismembrane allows the hepatocytes in the Layer Bx without coming in directcontact with them.

V. Layer Cx:

These microfluidic channels is used to flow the Plasma Portion from themodule I to provide the tissue, cells, stem cells and other neededtissue components (stem cells as well as ECM) in Micro-reservoirs macroand micronutrients requirements as well as the glucose through amembrane (layer Mh-HMWCO membrane).

VI. Layer Mh:

The high molecular weight cut-off membrane (HMWCO) separates the twomicrofluidic layers and provides the MSC, tissue, cells, stem cells withmacro and micronutrients requirements as well as the glucose. Thismembrane allows the tissue, cells, and stem cells in the Layer Bxwithout coming in direct contact with the immune components of theplasma or blood.

VII. Layer Bx:

These Microfluidic channels holds hepatocytes and other needed tissuecomponents (stem cells as well as ECM) in Micro-reservoirs. This layeras well as other similarly designed layers (Bx1, Bx2, Bx3, etc.) willreceive not come in contact with the Serum Portion from previous moduleThis fluid will diffuse through a membrane (layer Mh-HMWCO membrane) toprovide the microencapsulated MSC/Hepatocytes with macro andmicronutrients requirements as well as the glucose.

VIII. Layer Me:

The Membrane Oxygenator that is a typical Extra Corporeal MembraneOxygenator This layer is a membrane that separates the two microfluidiclayers and allows the RBC portion in the Layer B to provide oxygen forthe microencapsulated hepatocytes in the Layer A without direct intactwith them.

IX Layer Ax:

Microfluidic channels for the passage of RBC portion in parallel to thehepatocytes This layer as well as other similarly designed layers (Ax1,Ax2, Ax3, etc.) will receive the RBC rich portion from the previousmodule. This fluid will support the vital oxygen needed for the properfunctioning of the microencapsulated hepatocytes. The oxygen will flowthrough the ECMO membrane (Layer Me-ECMO membrane).Many repeats all these eight layers of the PDMS chips and membranes thatmake up a hepatic unit will make up the Bio-artificial liver ofdifferent sizes for different body sizes.

Each Construct=1 Bioreactor Organ (Hepatic) Unit/Module

First Design Module: (the Cellular Portion and Plasma Portion from thePS Module are Directed to this BR Module Microfluidic Channels

1^(st) Layer: microfluidic channels   Ax Layer/Red Cell Portion 2^(nd)Layer   Mxe Layer/ECMO Membrane 3^(rd) Layer:   microfluidic channels  Bx Layer/Hepatocyte Complex 4^(th) Layer   Mxh Layer/HMWCO Membrane5^(th) Layer: microfluidic channels   Cx1 Layer/Plasma Portion 6^(th)Layer   Mxh Layer/HMWCO Membrane 7^(th) Layer: microfluidic channels  Bx Layer/Hepatocyte Complex 8^(th) Layer   Mxe Layer/ECMO Membrane9^(th) Layer: microfluidic channels   Ax Layer/Red Cell Portion

Each Construct=1 Bioreactor Organ (Hepatic) Unit/Module First DesignModule: (the Cellular Portion is Returned to the Patient and PlasmaPortion from the PS Module is Only Directed to this BR Module

1^(st) Layer: microfluidic channels; Media/Plasma Compartment 1^(st)Membrane   HMWCO Membrane > 500 KDa 2^(nd) Layer: microfluidic channels;  Live Hepatocyte Compartment 2^(nd) Membrane   HMWCO Membrane > 500 KDa3^(rd) Layer: microfluidic channels; Media/Plasma Compartment

Second Design MCAL Technology Based Chipset Bioreactor (BR) Module

Use of whole blood; No direct flow of plasma over the tissue/cells/stemcells/MSC/etc. (here hepatocytes as example)This module is a repetition of four layers of microfluidic microchannelchip and semipermeable membranes that make up the hepatic unit which areconstructed as follow:

I. Layer A:

Microfluidic channels that pass through hepatocytes in Micro-reservoirs.[This layer as well as other similarly designed layers (A1, A2, A3,etc.) will receive the Serum Portion from previous module. This fluidwill bathe and provide the microencapsulated MSC/Hepatocytes with macroand micronutrients requirements as well as the glucose.]

II. Layer Me:

The Membrane Oxygenator that is a typical Extra Corporeal MembraneOxygenator. [This layer is a membrane that separates the twomicrofluidic layers and allows the RBC portion in the Layer B to provideoxygen for the microencapsulated hepatocytes in the Layer A withoutdirect intact with them.]

III. Layer B:

Microfluidic channels for the passage of RBC portion in parallel to thehepatocytes [This layer as well as other similarly designed layers (B1,B2, B3, etc.) will receive the RBC rich portion from the previousmodule. This fluid will support the vital oxygen needed for the properfunctioning of the microencapsulated hepatocytes.]

IV. Layer Me:

The Membrane Oxygenator that is a typical Extra Corporeal MembraneOxygenator [This layer is a membrane that separates the two microfluidiclayers and allows the RBC portion in the Layer B to provide oxygen forthe microencapsulated hepatocytes in the Layer A without direct intactwith them.]Repeat all four layers that form a unit generate different sizes ofbioartificial liver Hence the multilayer microfluidic module isschematically presented as follows:

Each Construct=1 Bioreactor Organ (Hepatic) Unit/Module Third DesignModule

1^(st) Layer: microfluidic channels   A Layer/Hepatocyte Complex 2^(nd)Layer   Me Layer/ECMO Membrane 3^(rd) Layer: microfluidic channels B₁Layer/RBC Cell Portion 4^(th) Layer   Me Layer/ECMO Membrane 5^(th)Layer: microfluidic channels A Layer/Hepatocyte ComplexThese above schematics are some simple designs for the microfluidicchannels/chambers. These channels and microreservoirs can be designed inmany exotic shapes, sizes and depths to improve the biomimetic componentof these two bioreactor modules (MCAL Technology based microfluidicchipset bioreactor organ unit/module.

In one embodiment, the bio-artificial organ/tissue such as liver,kidney, pancreas and etc. (Liver is used as example here) 144 mayinclude several modules disposed either serially or continuously on thesame blood or dialysate microfluidic chip Though in other embodiments,the bio-artificial organ 144 may be disjointed on different chipsetsthat are connected serially to emulate any human organ such as humanliver lobules. Those skilled in the art will recognize that largecollection of artificial organ units such as liver lobules make up anartificial organ most specifically in this example the liver. Due to thefact these organ modules/units (i.e. liver lobules here for liver) canbe constructed on different microfluidic chips, the ultimate designwould have the capability of replacing any one of these chips 104, 106if they fail to work properly, without disrupting the function of theother liver units.

In one possible embodiment, the bio-artificial organ-(here for exampleliver-144 comprises a microfluidic bioreactor having a macro-chamberthat—may have various shapes and forms including a rectangular shapedchamber, consisting of several major microfluidic components integratedtherein. The microfluidic bioreactor includes two modules: a plasmaseparator module and a bioreactor module. Various exotic designs may bepossible for the artificial liver (or other artificial organs)microfluidic channels 146. The bio-artificial organ-liver-144 mayinclude a microfluidic and biomimetic designed bio-artificial kidney orliver replacement for an In Vivo and/or Ex Vivo use Further advantageousof the microfluidic bio-artificial organ (liver) 144 are that it isdesigned to be: modular, scalable, Immunoisolated (no need forimmunosuppression), well-oxygenated, and well-nourished. It should benoted that this scheme and arrangement maybe used to develop variousnumbers of bioartificial bioreactors emulating various organs such askidney, pancreas, bone marrow, etc.

The bio-artificial bioreactor organ (any organ however, here for exampleliver tissue is used)-liver-144 may include a plurality ofbio-artificial micro-channels 146 and a plurality of bio-artificialmicroreservoirs 148 a, 148 b for carrying and storing tissue, tissuecomponents, cells, stem cells, structural components of tissue andsupport, whole blood and/or its components, plasma and its components134 and any liquids such as dialysate, modified dialysate containingcharcoal and/or resin, nutritional supports liquids containing macro-and/or micro-nutrients, oxygen, growth factors, hormones and etc. 116.The bio-artificial micro-channels 146 and a plurality of bio-artificialmicroreservoirs 148 a, 148 b are configured into myriad exotic shapes,sizes and depths to improve the biomimetic component of abio-artificial-any tissue/organ-such as liver 144. In some embodiments,the micro-channels 146 and the micro-reservoirs 148 a, 148 b comprise amicron size dimension ranging from 10-1000 micron and different heightsto maximize diffusion and convection of the desirable substances fromoxygen to micro- and macro-nutrients to and from the tissue componentsand cells (live cells/tissues) in the micro-reservoir. Additionally thesurface of these chambers/reservoirs/channels will be modified ifnecessary and covered with appropriate and necessary supporting materialsuch as ECM/Collagen material and etc. to make the tissue/cells suchliver such as hepatocyte/MSCs/Stem cells grow and stay viable.

The bio-artificial bioreactor organ-liver-144 has a special design withat least two main permutations. (Note; this bioreactor can be used forconstructing any bio-artificial bioreactor organs such as pancreas,kidney, liver and etc. however, for example liver cells/hepatocytes areused here). This permutation is based on the simple option of where todirect the serum portion output from the plasma separator module. Thereare basically two main designs: an indirect exposure of the cells withserum portion. A direct exposure of the cells with serum portion. Thoughin some embodiments, there could be other permutation of these twodesigns using microfluidic chipset modules.

The bio-artificial bioreactor organ/tissue (for example liver) 144 mayinclude several modules disposed either serially or continuously on thesame blood/tissue or fluid/gas/dialysate microfluidic chip. Thismicrofluidic module utilizes a plasmapheresis membrane over an inert andbiocompatible polymer used in microfluidic manufacturing such as PDMSbased channels to perform a plasmapheresis and plasma separation.Thereby, the input of the whole blood through this module will have twooutputs 1) the cell portion (C.P.), which mainly contains the cellularcomponents of the whole blood in small amount of plasma 2) the plasmaportion (P.P.), which is devoid of any cellular elements. The C.P.output is then immediately directed to the bioreactor construct is aseparate line, while the P.P. is directed to the bioreactor after goingthrough the module 2.

In the microfluidic module embodiment, whole blood enters thebio-artificial bioreactor organ/tissue-(here shown for liver) 144. Thefirst module of this device is where plasma portion (P.P) as well ascellular portion (C.P) components of the whole blood is separated. Thisis accomplished using a plasmapheresis membrane which has high molecularweight cut off membrane characteristics. The P portion is furtherseparated into a Rich Plasma Portion (RPP) and Serum Portion (SP)without the plasma proteins. The RPP will be returned to the patient.The S portion which contains the micro- and macro-nutrients which arediverted to the next module. The C.P portion is further separated intoRBC portion and the WBC/Platelets portion. The WBC+Platelets portion isreturned to the patient. The RBC portion is directed to the next module.The next module is an inert and biocompatible polymer used inmicrofluidic manufacturing such as multilayer PDMS construct that hasmultiple copies of a two layered microfluidic channels that arealternating while being separated by Extracorporeal Membrane Oxygenation(ECMO) membranes used here for oxygenation.

Though in other embodiments, the bio-artificial bioreactororgan/tissue-here used liver as an example 144 may be disjointed ondifferent chips that are connected serially to emulate human liverlobules. This microfluidic Bioreactor utilizes an inert andbiocompatible polymer used in microfluidic manufacturing such asmultilayer PDMS construct to achieve: a) Oxygenate and provide nutrientsas well as removal of the CO2 using the C.P. which has a highhematocrit. The C.P. is directed to the outer two layers of thebioreactor (see bioreactor function and design). The nutrient and theoxygen is delivered via two permeable membrane; and b) To bathe the livecells/tissues such as hepatocytes in the hydrogel with the “dialyzed”P.P. from module I this will enter the central layer of the bioreactor.Hence the toxins removed by the bioreactor.

Those skilled in the art will recognize that large collection ofartificial organ/tissue modules such as liver modules (lobules) make upan artificial organ such as liver. This holds true regarding otherorgans such as kidney, pancreas. Due to the fact these cells/tissues(here liver lobules) can be constructed on different microfluidic chips,the ultimate design would have the capability of replacing any one ofthese chips if they fail to work properly, without disrupting thefunction of the other tissue/organ units/modules-here liver units.

The bio-artificial liver 144 has a second design. The second design alsohas a plasma separator and a Bioreactor. However the layering isaltered. In the plasma separator module, whole blood enters thebio-artificial liver 144. The first module of this device is whereplasma portion (P.P) as well as cellular portion (C.P) components of thewhole blood is separated. This is accomplished using a plasmapheresismembrane. The P portion is further separated into a Rich Plasma Portion(RPP) and Serum Portion (SP) without the plasma proteins. The RPP willbe returned to the patient. The S portion which contains the micro andmacro nutrients are diverted to the next module. The C portion isfurther separated into RBC portion and the WBC/Platelets portion. TheWBC+Platelets portion is returned to the patient. The RBC portion isdirected to the next module. The next module is a microfluidicmultilayer PDMS construct that has multiple copies of a two layeredmicrofluidic channels that are alternating while being separated by ECMOmembranes.

Bio-Artificial Bioreactors for Organ Support

This is Simply a Combination of the Bioreactor Organs in Series withthe 1) Combined Microfluidic Kidney and Liver Dialysis Device or 2)Mobile, Modular and Scalable Microfluidic-Based Kidney and/or LiverDialysis Device.

The Artificial Bioreactor Organs (Liver/Kidney/Pancreas etc.)

The Artificial Lung using various MCAL technology based microfluidicchipset units/modules

The MCAL Technology is used to design a more efficient and/or portablemicrofluidics-based Artificial Lung. The multiple goals of thismicrofluidic Artificial Lungs are:

To increase efficiencyTo increase surface areaTo decrease volumeTo increase SA/V ratioTo increase diffusionTo reduce the size of the unitTo achieve this we will tap into the microfluidic technology

The First Design two to multilayered design (Using Whole Blood)

1st Layer: Microfluidic channels: O1 Layer/(Air/oxygen channels)2nd Layer/only a membrane: M1 Layer/(ECMO Membrane Layer)3rd Layer: Microfluidic Channels: A1 Layer/(Whole Blood Cell channels)4th Layer/only a membrane: M2 Layer/ECMO Membrane Layer5th Layer: Microfluidic channels: 02 Layer/(Air/oxygen channels)Nth layer repeating O, M and A layers repeatedly as needed.

Second Design two to multilayered design (Fractionated Blood)

Module 1: The Plasma Separator

1. Whole blood enters the Artificial Lung Device.2. The first module of this device is MCAL Technology microfluidicchipset-PS Module where plasma portion (P.P) as well as cellular portion(C.P) components of the whole blood is separated.3. This is accomplished using a plasmapheresis membrane.4. The Plasma portion is returned to the patient.7. The C.P. is further separated via another MCAL Technologymicrofluidic chipset-PSModule into RBC portion/Platelets portion and theWBC.8. The WBC+portion is returned to the patient.9. The RBC+Platelet portion is directed to the next module.

The next module is a microfluidic multilayer PDMS construct that hasmultiple copies of a three-layered microfluidic channels that arealternating while being separated by ECMO membranes.

Module 2: The Blood Oxygenator

1st Layer: Microfluidic channels: 01 Layer/(Air/oxygen channels) 2ndLayer/only a membrane: M1 Layer/ECMO Membrane Layer3rd Layer: Microfluidic channels: A1 Layer/Pure RBC+Portion channels)4th Layer/only a membrane: M2 Layer/ECMO Membrane Layer5th Layer: Microfluidic channels: O2 Layer/(Air/oxygen channels) Nthlayer repeating O, M and A layers repeatedly as needed.

The Bio artificial Organs (Artificial Liver is used here as an example)

PS Module: Plasma Separation Function. This microfluidic chipset module(PS module/unit) will use a plasmapheresis membrane over a microfluidicPDMS based channels to perform a plasmapheresis. Thereby, the input ofthe whole blood through this module will have two outputs 1) the cellportion (C.P.), which mainly contains the cellular components of thewhole blood in small amount of plasma 2) the plasma portion (P.P.),which is devoid of any cellular elements. The C.P. output is thenimmediately directed to the bioreactor construct is a separate line,while the P.P. is directed to the bioreactor after going through the Omodule #2.

Chipset BR module (Bioreactor Chipset): Oxygenation of the hepatocytesin Bioreactor—This microfluidic Bioreactor will use a multilayer inertand biocompatible polymer used as microfluidic substrate such PDMSconstruct to achieve:

Oxygenate and provide nutrients as well as removal of the CO2 using theC.P. which has a high hematocrit. The C.P. is directed to the outer twolayers of the bioreactor. The nutrient and the oxygen is then deliveredvia two semipermeable membranes.

To bathe the hepatocytes (other organ/tissue/cells) in the hydrogel, the“dialyzed” P.P. from module #4 which will enter the central layer of thebioreactor. Hence the toxins left over from the dialysis device-thecombined microfluidic-based kidney and Liver dialysis device isprocessed by any one of the bioreactors (kidney, liver, lung, andpancreas).

The two portions are then mixed and returned to the patient as wholeblood. Note: may place a module here to clear metabolites from P.Pbefore returning it to the patient.

Module #2: The P.P. portion is directed to this module and via a highlypermeable dialysis membrane (high flux) will perform a very intensivehemodiafiltration which will perform an intensive ultrafiltration(convective dialysis) as well as diffusive dialysis. In the process thedialysate is passed in cross-flow against the P.P. and will have anoutput of U/F plus spent dialysis. The dialyzed P.P. will be directed tothe next module.

Module #3: The Tubular Portion (Clearance Function) The P.P. will enterthis module and will come in direct contact with reservoirs of resin andcharcoal that are embedded into the PDMS chipset. Each channel has itsown dedicated reservoir. In addition, to avoid saturation of thesereservoirs of the charcoal and resin, a dialysate solution containingcharcoal is used to regenerate these reservoirs. To achieve this, thisspecial dialysate is run in a cross-flow pattern against a high fluxdialysis membrane. The P.P. will be directed to the next module.

Module #4: The Tubular Section (Clearance Function) The P.P. is directedto a chip module with a special design with a multi-layer PDMScontaining 5 layers. The middle layer is sandwiched between two mirrorimage layers. The P.P. is located in the central layer which issandwiched between two identical layers containing dialysate+Albumin.These three layers are sandwiched between two identical layerscontaining dialysate+charcoal. The four membranes separating all fivelayers have characteristics of a High Molecular Weight Cut-Off dialysismembrane in order to achieve albumin dialysis.

A d construct of a biomimetic microfluidic Liver is a combination of 4distinct modules that are connected in series as was described above.The whole blood is diluted in 1:1 to 1:4 whole blood/replacement fluidratios which is then directed to run through the 4 distinct modules toachieve a very high quality and efficient dialysis.

Basic Design of a Liver Unit:

Each one of these artificial nephrons will have an approximate length of1-12 cm.

L: 1-12 cm

W: 100-1000 um (100 um with its walls)

D: 10-50 um (shallow depth for faster diffusion)

All these liver lobules/units are placed in parallel to each other onthe same chipset and on the same layer. Additional layers are added toincrease the number of these liver units to emulate the native liver.

Looking now at the block diagram of FIG. 17, the blood is circulatedfrom the body and through a bio-artificial kidney dialysis system 150.Similar as to the microfluidic units 102 a-d, the micro-pumps 130 a-cforce the blood from the body to a bio-artificial kidney 152. In theillustrated embodiment, the bio-artificial kidney 152 is used fordialysis. Though, the bio-artificial liver 144 may also be used. Ineither case, they operate substantially the same as discussed above withthe microfluidic units 102 a-d. The contaminated dialysate 122 from thedialysis process in the bio-artificial kidney 152 may be redirected toan external filtering process consisting of: a forward dialyses 138, areverse osmosis 140, and a waste reservoir 142 for catching the water,toxins, and small electrolytes. From this external filtering process,the partially filtered contaminated dialysate 122 flows to themicrofluidic regenerating housing 128 containing a plurality ofmicrofluidic regenerating units/modules 118 a-c. The regenerateddialysate 120 then flows back to the bio-artificial liver 144 forfurther dialysis processing. A dialysate vial 136 may be used to addfresh dialysate to the regenerated dialysate 120.

Bio-Artificial Organ Support Systems (Combinations of #3 with #1 or #2)

The MCAL Technology core technology is further used to design a moreefficient microfluidics based Bio-Reactor and Bio-artificial organsupport system. The multiple goals of this microfluidic Bio-reactor isto replace/support failing organ/tissue Furthermore, this bio-reactorcan be placed in series with MFC building blocks-such kidney and/orliver dialyzer to form a more complex Bio-Artificial organ support

The Overall Design of the Bioreactor Utilizing the MCAL Technology BasicUnits

The bioreactors will be used to produce biomimetically designedmicrofluidic-based various artificial organs such as Liver, Kidney,Lungs or Pancreas and etc. The microfluidic chipset BR module can befilled with different tissues, cells, stem cells and supportingstructures for preserving the living cells/tissue. For example, theartificial liver is consisting of several modules which are placedserially either continuously on the same chipset, or disjointed ondifferent chipsets that are connected serially to emulate a human liverlobule. A large collection of these artificial liver lobules” make up anartificial liver. The modules are as follows: (See drawing #1, #2, #3#4, #5 & #6) (Note: the whole blood may be diluted using replacementfluid before entering the module #1)

Microfluidic Based on Demand Intravenous Fluid and Dialysate Generator:

Microfluidic Intravenous Fluid Generator is intended to be an integratedmedical component system capable of producing a variety of packaged i.v.fluids as well as high quality ultra-pure water supply for dialysategeneration on demand and in quantities large enough to support fieldmedical treatment facilities (MTF) that provide emergency resuscitativesurgery and critical care.

The objective of microfluidic i.v. Fluid/Dialysate Generator is a noveldesign of using various microfluidic chipset units (modules) based onMCAL Technology to design and develop high quality ultra-purewater-source processing device consisting of integrated medical gradecomponents. The device will be capable of producing packaged i.v. fluidsfor use by medical personnel in forward-deployed environments supportinginitial and sustained military operations.

Starting with any quality tap water from any available water source,this microfluidic device-a stand-alone microfluidic Intravenous FluidGenerator device will produce a variety of i.v. fluid solutions whichincludes but not limited to dialysate fluids, replacement fluids, normalsaline, half saline, dextrose and lactated Ringers Additionally, thisdevice will be able to be operated by a single person.

For generating ultrapure water from tap water for intravenous use ordialysate use . . . This will allow to generate different types of i.v.fluids for medical use

Design of the microfluidic Intravenous Fluid Generator:

Two Designs:

1. Ro system with prefilled special bags with specified electrolytes2. Microfluidic RO system plus microfluidic mixer (optional)

The Overall Process:

The process of producing ultrapure water from tap water will be acombination of the following parts/layers. Of course this sterile watercan be used to generate different types of i.v. fluid solutions usingplastic bags with certain combination of electrolytes. When specificamount of fluid is add, the final concentration will be one of the sevenmajor i.v. fluid solution bags ready for administration.

I. The Ultrafiltration Membrane Layer: (optional as first layer)The feed water flows over the first layer which consists of anultrafiltration membrane.

II. The Activated Charcoal Layer:

The cleaned water from the previous layer then flows over the secondlayer which contains activated charcoal.

III. The Nano-filtration Membrane Layer:

The cleaned water from the previous layer then flows over the thirdlayer which consists of a nanofiltration membrane.

IV. The RO Membrane Layer:

The cleaned water from the previous layer then flows over the fourthlayer which consists of a R.0. membrane.

V. The Deionizing Layer:

The Cleaned water from the previous layer then flows over the fifthlayer which consists of a mixed-bed ion exchange resin.

The Ultrafiltration Membrane Layer:

The feed water flows over this last layer which consists of anultrafiltration membrane.

Different Configurations of the Microfluidic Water Purification System

Configurations/Modules:

I. Multilayer microfluidic chipset with its channels packed withmicroporous and mesoporous activated carbon. This module is for thecarbon filter portion.II. A multilayer microfluidic chipset designed to be used as the ROsystem. This three layered chipset module is composed of two mirrorimage microfluidic layers (inert and biocompatible polymer used asmicrofluidic substrate such as PDMS layers), which sandwich a centralmicrofluidic layer (i.e. PDMS layer) with its both side covered with ROmembranes. The flow of feed water is through the channels of the centralcompartment which produces ultrapure water through the outer two layersleaving behind brine. (Design #)III. Continuous Electrodeionization (CED) chipset designed to be used asthe deionization of the RO system output for total removal of anions andcations. This three layered cell is composed of two mirror image PDMSlayer which are based on two thin layers of electrodes. One layer isplaced on an electrode connecting to the DC current acting as an anode,and the other layer is placed on another electrode acting as thecathode.

The third layer's channels-the centralized PDMS-are filled with mixedbed ionic resins and are covered on both sides with specializedpermeable ion exchange membranes. One side is covered with an anionicmembrane and the other side with a cationic membrane. This combinationis then sandwiched between the other two layers making sure that thePDMS layer with the positive electrode is placed on top of the centralPDMS covering the cationic membrane side and the other one with thenegative electrode is placed so it covers the anionic membrane.

A multilayer top down flow PDMS cell consisting of the followings (ordermaybe change to increase the fidelity of each step.

Feed water flows over the first layer composed of tightly micro- andmesoporous activated carbon. This layer is separated from the next layerby a microfiltration membrane. The next layer is a PDMS layer packedwith mixed bed ion exchange resins. The water flows over this layer andmoves through a nanofiltration membrane which separates it from the nextlayer. This PDMS layer is where RO occurs. The space is not filled withanything allowing the filling up the space for continuous RO waterproduction. The next layer is an optional repeat of the first two layerswith their corresponding membranes. These extra layers are placed as abackup in order to avoid super saturation and release of some of thecontaminants from the 1st and 2nd layers These layers (repeat layers)are separated from the outflow channels by an ultrafiltration membrane.

1st layer: PDMS chips with many parallel channels are tightly packedwith the activated carbon.

2nd layer: An ultrafiltration membrane is place at this level separatingthe first PDMS from the next

3rd layer: PDMS chips with many parallel channels that act as areservoir to build up the water for the slower process of the ROprocess. This PDMS chip is separated from the next layer via the ROmembrane.

4th layer: specialized multilayer PDMS which is assembled in a top downfashion but is placed in this complex multilayered water purificationdevice in a right (90 degree) angel and perpendicular manner to theother layers.

This Multilayered PDMS with its outer layers covered with electrodes oneach side to act as an anode and cathode when connected to the DCcurrent to run the continuous electrodeioniziation process. In betweenthere are multiple layers of alternating anionic and cationic permeableion exchange membranes. In addition, every other space between thesealternating anionic and cationic membranes is filled with mixed bed ionexchange resins. The alternating spaces that do not contain the mixedion exchange resins are closed off, therefore, all the concentratedwater brine is accumulated and is drained off on the side. Meanwhile thepure water that is generated is forwarded to the next layer.

5th layer: this layer is an ultrafiltration membrane that is placed toensure bacteria and other pathogens are effectively removed. The outflowof this layer is the ultrapure water that is used for generatingultrapure dialysate fluid for the purpose of hemodialysis. See allattached Figures and Diagrams.

It is significant to note that the ultrapure water produced will also beused to generate ultrapure dialysate fluid, using a microfluidic chipthat uses a concentrated acid and base to combine it with the pure waterin pre-specified ratio. (Microfluidic dialysate proportioning system).

What I claim is:
 1. A modular microfluidic dialysis system, comprises,the system comprising: a plurality of microfluidic chipset units, theplurality of microfluidic chipset units configured to enable dialysis ofblood, or plasma, the plurality of microfluidic chipset units arrangedin modular configuration for enabling scalability, the plurality ofmicrofluidic chipset units at least partially fabricated from any inertand biocompatible polymers used for microfluidic substrate such aspolymeric organosilicon compound, the plurality of microfluidic chipsetunits comprising: Various modular and scalable biomimetically designedmicrofluidic-based multilayered micro-channels separated by variousbasic semipermeable membranes configured to carry blood, plasma, fluidor various dialysate compositions, various multilayered the microfluidicchipset units comprising a plurality of micro-pumps, the plurality ofmicro-pumps configured to pump the blood and its components, plasma andits components to and from the microfluidic chipset units, the pluralityof micro-pumps further configured to pump the various fluid compositionsand dialysate solutions including the albumin, lipid, charcoal and/orresin solutions, to and from the microfluidic chipset units, variousmultilayered the microfluidic chipset units comprising a plurality ofmicro-channels, the plurality of micro-channels defined by a topographyhaving a substantially microvasculature configuration, the plurality ofmicro-channels further defined by varying widths, the plurality ofmicro-channels configured to carry whole blood and its components,plasma and its components or hold various tissues and their components,cells, stems cells, components or plasma to and from a bloodmicrofluidic chip, the plurality of micro-channels further configured tocarry the fluid to and from a dialysate microfluidic chip; at least twobasic semipermeable membranes, the at least two basic semipermeablemembranes disposed between multilayered the r microfluidic chipset unit,the at least two basic semipermeable membranes configured to form apermeable barrier between the fluid and the blood, tissue, or plasma,the at least two basic semipermeable membranes further configured toenable passage of water, electrolytes, macro- and micro-nutrients,growth factors, glucose, oxygen, toxins and water from the blood,tissue, or plasma in the blood microfluidic chip to the fluid in thedialysate microfluidic chip; a plurality of microfluidic regeneratingchipset units, the plurality of microfluidic regenerating chipset unitsconfigured to at least partially filter contaminated fluid and spentdialysate received from the microfluidic chipset units, the plurality ofmicrofluidic regenerating units further configured to return regeneratedfluid and fresh dialysate to the dialysate microfluidic chip; and a datatransmission portion, the data transmission portion configured to enablereal time monitoring of physiological parameters of the body andmechanical parameters of the system.
 2. The system of claim 1, whereinthe at least two basic semipermeable membranes are arranged in at leasttwo permutations, the at least two permutations configured to enabledevelopment of an organ or a bio-artificial organ, and replacement of anorgan or bioartificial organ.
 3. The system of claim 1, wherein the atleast two basic semipermeable membranes comprises at least one of thefollowing: a hemodialysis filter, an ultrafiltration filter, a plasmaseparation or plasmapheresis filter, a hemoperfusion filter, an albumindialysis filter, a diafiltration filter, a hemodiafiltration filter, adialysis regeneration filter, an oxygenation filter, a hemodialysis/highefficiency filter, an albumin dialysis and regeneration filter, a tissuesupport filter, the tissue support filter comprising a high molecularweight cutoff membrane, a reverse osmosis filter, a forward osmosisfilter, an electrodeionization filter, an electrodialysis filter, anelectrofiltration filter, and a lipid dialysis filter.
 4. The system ofclaim 1, wherein the fluid comprises at least one of the following:various liquid compositions, various dialysate compositions includingalbumin, lipid and charcoal and resin solutions, plasma, oxygen, blood,and growth hormones, macro- and micro-nutrients.
 5. The system of claim1, wherein the topography of the plurality of micro-channels include atleast one member selected from the group consisting of: straight,parallel, crisscross, fractal, loop, and branched.
 6. A modularmicrofluidic dialysis system, comprises, the system comprising: aplurality of microfluidic units, the plurality of microfluidic unitsconfigured to enable dialysis of blood, tissue, or plasma, the pluralityof microfluidic units arranged in modular configuration for enablingscalability, the modular configuration of the system configured suchthat about 20-40 microfluidic units form a microfluidic construct, themodular configuration of the system further configured such that about 5microfluidic constructs form a microfluidic module, the microfluidicmodule configured to position inside a microfluidic housing, theplurality of microfluidic units at least partially fabricated frompolydimethylsiloxane, the plurality of microfluidic units comprising: ablood microfluidic chip and a dialysate microfluidic chip, the bloodmicrofluidic chip configured to carry blood, tissue, or plasma, thedialysate microfluidic chip configured to carry a fluid, the bloodmicrofluidic chip and the dialysate microfluidic chip comprising aplurality of micro-pumps, the plurality of micro-pumps configured topump the blood, tissue, or plasma to and from the blond microfluidicchip, the plurality of micro-pumps further configured to pump the fluidto and from the dialysate microfluidic chip, the blood microfluidic chipand the dialysate microfluidic chip further comprising a plurality ofmicro-valves, the plurality of micro-valves configured to regulate theflow of the fluid and the blood, tissue, or plasma, the bloodmicrofluidic chip and the dialysate microfluidic chip further comprisinga plurality of micro-channels, the plurality of microchannels defined bya topography having a substantially microvasculature configuration, theplurality of micro-channels further defined by varying widths, theplurality of microchannels configured to carry the blood, tissue, orplasma to and from the blood microfluidic chip, the plurality ofmicro-channels further configured to carry the fluid to and from thedialysate microfluidic chip; and at least two basic semipermeablemembranes, the at least two basic semipermeable membranes disposedbetween the blood microfluidic chip and the dialysate microfluidic chip,the at least two basic semipermeable membranes configured to form apermeable harrier between the fluid and the blood, tissue, or plasma,the at least two basic semipermeable membranes further configured toenable passage of toxins and water from the blood, tissue, or plasma inthe blood microfluidic chip to the fluid in the dialysate microfluidicchip; a plurality of microfluidic regenerating units, the plurality ofmicrofluidic regenerating units configured to at least partially filtercontaminated fluid received from the dialysate microfluidic chip, theplurality of microfluidic regenerating units further configured toreturn regenerated fluid to the dialysate microfluidic chip; and a datatransmission portion, the data transmission portion configured to enablereal time monitoring of physiological parameters of the body andmechanical parameters of the system.
 7. The system of claim 6, whereinthe at least two basic semipermeable membranes are arranged in at leasttwo permutations, the at least two permutations configured to enabledevelopment of an organ or a bio-artificial organ, and replacement of anorgan or bioartificial organ.
 8. The system of claim 6, wherein the atleast two basic semipermeable membranes comprises at least one of thefollowing: a glomerular filter, an ultrafiltration filter, a plasmaseparation or plasmapheresis filter, a hemoperfusion filter, an albumindialysis filter, a diafiltration filter, a hemodiafiltration filter, adialysis regeneration filter, an oxygenation filter, a hemodialysis/highefficiency filter, an albumin dialysis and regeneration filter, a tissuesupport fitter, the tissue support filter comprising a high molecularweight cutoff membrane, a reverse osmosis filter, a forward osmosisfilter, an electrodeionization an electrodialysis filter, anelectrofiltration filter, and a lipid dialysis filter.
 9. The system ofclaim 6, wherein the fluid comprises at least one of the following:fluid, various types of dialysate compositions, plasma and itscomponents, oxygen, blood, and nutrients.
 10. The system of claim 6,wherein the topography of the plurality of micro-channels include atleast one member selected from the group consisting of: straight,parallel, crisscross, fractal, loop, and branched.
 11. The system ofclaim 6, wherein the plurality of micro-valves are configured to closeif the microfluidic module is not disposed in an operable orientationinside the microfluidic housing.
 12. A modular microfluidic dialysissystem, comprises, the system comprising: a plurality of microfluidicunits, the plurality of microfluidic units configured to enable dialysisof blood, tissue, or plasma, the plurality of microfluidic unitsarranged in modular configuration for enabling scalability, theplurality of microfluidic units at least partially fabricated from apolymeric organosilicon compound, the plurality of microfluidic unitscomprising: a blood microfluidic chip and a dialysate microfluidic chip,the blood microfluidic chip configured to carry blood, tissue, orplasma, the dialysate microfluidic chip configured to carry a fluid, theblood microfluidic chip and the dialysate microfluidic chip comprising aplurality of micro-pumps, the plurality of micro-pumps configured topump the blood, tissue, or plasma to and from the blood microfluidicchip, the plurality of micro-pumps further configured to pump the fluidto and from the dialysate microfluidic chip, the blood microfluidic chipand the dialysate microfluidic chip further comprising a plurality ofmicro-valves, the plurality of micro-valves configured to regulate theflow of the fluid and the blood, tissue, or plasma, the bloodmicrofluidic chip and the dialysate microfluidic chip further comprisinga plurality of micro-channels, the plurality of microchannels defined bya topography having a substantially microvasculature configuration, theplurality of micro-channels further defined by varying widths, theplurality of microchannels configured to carry the blood, tissue, orplasma to and from the blood microfluidic chip, the plurality ofmicro-channels further configured to carry the fluid to and from thedialysate microfluidic chip; and at least two basic semipermeablemembranes, the at least two basic semipermeable membranes disposedbetween the blood microfluidic chip and the dialysate microfluidic chip,the at least two basic semipermeable membranes configured to form apermeable barrier between the fluid and the blood, tissue, or plasma,the at least two basic semipermeable membranes further configured toenable passage of toxins and water from the blood, tissue, or plasma inthe blood microfluidic chip to the fluid in the dialysate microfluidicchip; and a plurality of microfluidic regenerating units, the pluralityof microfluidic regenerating units configured to at least partiallyfilter contaminated fluid received from the dialysate microfluidic chip,the plurality of microfluidic regenerating units further configured toreturn regenerated fluid to the dialysate microfluidic chip.
 13. Thesystem of claim 12, wherein the at least two basic semipermeablemembranes comprises at least one of the following: a hemodialysisfilter, ultrafiltration filter, a plasma separation or plasmapheresisfilter, a hemoperfusion filter, an albumin dialysis filter, adiafiltration filter, a hemodiafiltration filter, a dialysisregeneration filter, an oxygenation filter, a hemodialysis/highefficiency filter, an albumin dialysis and regeneration filter, a tissuesupport filter, the tissue support filter comprising a high molecularweight cutoff membrane, a reverse osmosis filter, a forward osmosisfilter, an electrodeionization an electrodialysis filter, anelectrofiltration filter, and a lipid dialysis filter.